NM_001042492.3:c.4330A>G

Variant names:

• chr17-31258500-A-G
• rs137854550
• NM_001042492.3:c.4330A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.4330A>G​(p.Lys1444Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1444M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 0.8352
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 U:1
• Conservation: PhyloP100: 8.91
• Publications: 53 publications found

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 37 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31258501-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 694609.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 17-31258500-A-G is Pathogenic according to our data. Variant chr17-31258500-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.4330A>G	p.Lys1444Glu	missense splice_region	Exon 32 of 58	NP_001035957.1
	NF1	NM_000267.4		c.4267A>G	p.Lys1423Glu	missense splice_region	Exon 31 of 57	NP_000258.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.4330A>G	p.Lys1444Glu	missense splice_region	Exon 32 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.4267A>G	p.Lys1423Glu	missense splice_region	Exon 31 of 57	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.4267A>G		splice_region non_coding_transcript_exon	Exon 31 of 58	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250882 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461410 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727002

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111826

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000189 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:12 Uncertain:1

Apr 17, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 02, 2017

Medical Genetics, University of Parma

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1423 of the NF1 protein (p.Lys1423Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 and neurofibromatosis-Noonan syndrome (PMID: 1568247, 11857752, 16380919, 16786508, 23244495, 27322474). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 336). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NF1 function (PMID: 1568247, 8264648, 22807134). For these reasons, this variant has been classified as Pathogenic.

Jun 03, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Oct 19, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP3.

Nov 12, 2024

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 11, 2024

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS3,PS4,PM2_sup,PM5_strong,PP2,PP3

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Jun 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys1444Glu variant in NF1 (p.Lys1423Glu on transcript NM_000267.3) has bee n previously reported in at least 5 individuals with Neurofibromatosis type 1 an d segregated with disease in 4 affected family members from 1 family (Li 1992, U padhyaya 1997, Upadhyaya 2004, Laycock-VanSpyke 2011 ). In addition, it has been identified as a somatic variant in individuals with colon adenocarcinoma, anapl astic astrocytoma, and myelodysplasitc syndrome (Li 1992). This variant has also been identified in 1/65426 European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs137854550). Please note that for diseases with variable expressivity, pathogenic variants may be present at a low frequency in the general population. Furthermore, in-vitro functional stud ies provide some evidence that this variant may impact protein function (Li 1992 , Poullet 1994, Thomas 2012). This variant is located in the last three bases of the exon, which is part of the 5? splice region, and computational tools sugges t a possible impact to splicing. However, in vitro assays and computational too ls may not accurately represent biological function. In summary, this variant m eets our criteria to be classified as pathogenic for neurofibromatosis type 1 in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studies and functional evidence.

Jan 16, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.91 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000336 /PMID: 1568247). Different missense changes at the same codon (p.Lys1444Arg, p.Lys1444Asn, p.Lys1444Gln, p.Lys1444Met, p.Lys1444Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068344, VCV000068345, VCV000404485, VCV000431637, VCV001739214 /PMID: 11735023, 12552569, 18546366, 29618358, 31595648). Therefore, this variant is classified as Pathogenic (PS1_S, PS2_S, PM2_M, PM5_M, PP3_P) according to the recommendation of ACMG/AMP guideline.

Jun 05, 2019

UAB Medical Genomics Laboratory, UAB Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 23, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 4 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar; Variant is located in a hotspot region or cluster of PATHOGENIC variants (DECIPHER); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change; This variant has been shown to be de novo in the proband by trio analysis (parental status confirmed). Additional information: Variant is predicted to result in a missense amino acid change from Lys to Glu; This variant is heterozygous; This gene is associated with autosomal dominant disease; Alternative amino acid change(s) at the same position are present in gnomAD (v4: 1 heterozygote(s), 0 homozygote(s)); Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis type 1 (MONDO:0018975); Variants in this gene are known to have variable expressivity. Disease manifestation can be extremely variable, even within a family (PMID: 20301288).

not provided Pathogenic:6

Sep 11, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in multiple individuals and families with NF1 in the published literature (PMID: 29415745 (2018), 23244495 (2012), 18546366 (2008), 16380919 (2005), 11857752 (2002), 9003501 (1997), 1568247 (1992)), including in a family where it segregated with disease (PMID: 1568247 (1992)). This variant has been reported as a de novo event (PMID: 27322474 (2016)). Functional data suggest that the variant is detrimental to normal protein function (PMID: 22807134 (2012), 16513807 (2006), 9219873 (1997), 9003501 (1997), 8264648 (1994)). Based on the available information, this variant is classified as pathogenic.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 03, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: reduced GTPase-activating protein activity (Li 1992, Poullet 1994, Thomas 2012); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16513807, 22807134, 8264648, 27322474, 1568247, 14722917, 18546366, 9003501, 22155606, 19845691, 23244495, 16380919, 9219873, 11857752, 29673180, 29415745, 31595648, 29625052, 16786508, 31730495, 31776437, 25486365, 33443663)

Jun 07, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 11, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including at least one apparent de novo. In some published literature, this variant is referred to as c.4330A>G, p.Lys1444Glu. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant significantly reduced the protein's ability to activate GTPase (PMID: 1568247, 8264648, 22807134). This is implicated in loss of p21 regulation, ras signaling interference and tumorigenesis. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure.

Neurofibroma;C0346326:Optic nerve glioma;C1860335:Axillary freckling;C1861975:Cafe au lait spots, multiple Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pheochromocytoma Pathogenic:1

Sep 14, 2022

Department of Medicine, University of Texas Health Science Center at San Antonio

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The following PIDs represent publications in which this variant has been detected and evaluated both in clinical contexts (patient-derived samples) and by in vitro experiments, and all of them support the pathogenic nature of this variant. These publications report on detection of this variant in germline disease (neurofibromatosis type 1) and as a somatic event in various cancer types. Moreover, there are multiple additional submissions to ClinVar that report this variant, mostly in the context of germline disease. We detected this variant as a somatic event accompanied by LOH of the wild-type allele in a patient that had a sporadic pheochromocytoma, but not neurofibromatosis type 1.

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Juvenile myelomonocytic leukemia Pathogenic:1

Dec 21, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Café-au-lait macules with pulmonary stenosis Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3,PS2,PP1,PS4

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1

Dec 17, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K1423E variant (also known as c.4267A>G), located in coding exon 31 of the NF1 gene, results from an A to G substitution at nucleotide position 4267. The lysine at codon 1423 is replaced by glutamic acid, an amino acid with similar properties. This mutation was detected in an NF1 family with perfect segregation among six (four affected who met NIH diagnostic criteria and two unaffected) family members (Li Y, et al. Cell 1992; 69(2):275-81). This mutation has also been detected in several individuals who met NIH diagnostic criteria for Neurofibromatosis type 1 (NF1) (Cassiman C et al. Clin. Genet., 2017 Apr;91:529-535; Cannon A et al. Orphanet J Rare Dis, 2018 Feb;13:31; Upadhyaya M, et al. Hum. Mutat. 2008; 29(8):E103-11; Thomas L, et al. Hum. Mutat. 2012;33(12):1687-96; Pros E, et al. Hum. Mutat. 2008;29(9):E173-93; Wang Q, et al. Hum. Genet. 2003;112(2):117-23; Stella A et al. Genes (Basel), 2018 Apr;9:) and in several individuals with Noonan syndrome features (De Luca A, et al. Am. J. Hum. Genet. 2005; 77(6):1092-101). Functional analysis of this alteration in an in vitro Ras-activation assay shows significantly elevated levels of activated Ras compared to wild type (Thomas L et al. Hum. Mutat. 2012 Dec;33:1687-96). Based on the supporting evidence, p.K1423E is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.92		Loss of MoRF binding (P = 0.0013)
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.97
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Benign	0.55
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137854550; hg19: chr17-29585518; COSMIC: COSV62204136; COSMIC: COSV62204136;