rs1187097568

Variant names:

• chr17-31232830-A-G
• rs1187097568
• NM_001042492.3:c.3445A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-31232830-A-G
• chr17-31232830-A-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.3445A>G​(p.Met1149Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1149R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 8.88
• Publications: 15 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 16 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 31 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 chr17-31232831-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 429001.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 17-31232830-A-G is Pathogenic according to our data. Variant chr17-31232830-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 527517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3445A>G	p.Met1149Val	missense_variant	Exon 26 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.3445A>G	p.Met1149Val	missense_variant	Exon 26 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3445A>G	p.Met1149Val	missense_variant	Exon 26 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251376 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: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:6

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1149 of the NF1 protein (p.Met1149Val). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 23656349, 24711935, 28706617, 31595648; internal data). ClinVar contains an entry for this variant (Variation ID: 527517). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. This variant disrupts the p.Met1149 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16944272, 27322474; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2022

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.3445A>G (p.Met1149Val) variant results in the substitution of a methionine at amino acid position 1149 with valine. This variant has been reported in at least 38 heterozygous individuals with neurofibromatosis type 1 (Koczkowska et al. 2020). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000046 in the European (Finnish) population (version 2.1.1). The Met1149 residue has been identified as a non-truncating hotspot in the gene (Koczkowska et al. 2020) with additional pathogenic variants that have been identified in patients with neurofibromatosis type 1 within two residues on each side of the variant. Three other amino acid changes due to missense variants at the Met1149 residue that have been reported in the literature and found in at least 13 individuals with neurofibromatosis type 1 (Koczkowska et al. 2020). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.3445A>G (p.Met1149Val) variant is classified as pathogenic for neurofibromatosis type 1. -

Apr 09, 2025

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2019

UAB Medical Genomics Laboratory, UAB Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:3

Feb 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP3+PP4+PM5+PP1_Moderate -

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1 NM_000267.3 exon 26 p.Met1149Val (c.3445A>G): This variant has been reported in the literature in multiple individuals with features of neurofibromatosis type I, segregating with disease in several affected family members (van Minkelen 2014 PMID:23656349, Domingues 2014 PMID:24711935, Koczkowska 2020 PMID:31595648). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:527517). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, this variant is classified as pathogenic based on the data above -

not provided Pathogenic:3

Mar 30, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: impaired ability to inhibit GTP-Ras activity (Long et al., 2022); This variant is associated with the following publications: (PMID: 23656349, 26681766, 28706617, 24711935, 29617658, 29095814, 31618753, 31370276, 25486365, 2121369, 22807134, 27322474, 29290338, 16944272, 31776437, 31595648, 33884301, 34694046) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1: PM2, PM5, PS4:Moderate -

NF1-related disorder Pathogenic:1

Mar 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.3445A>G variant is predicted to result in the amino acid substitution p.Met1149Val. This missense variant has been documented in several individuals with neurofibromatosis type 1 (Domingues et al. 2014. PubMed ID: 24711935; Gengel et al. 2017. PubMed ID: 28706617; Koczkowska et al. 2020. PubMed ID: 31595648). In addition, alternative missense changes at the same codon (p.Met1149Thr, p.Met1149Ile) have been documented to be pathogenic individuals with neurofibromatosis type 1 (Koczkowska et al. 2020. PubMed ID: 31595648; Evans et al. 2016. PubMed ID: 27322474; Griffiths et al. 2007. PubMed ID: 16944272) and are interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/527517/). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29559848-A-G). This variant is interpreted as pathogenic. -

Neurofibromatosis-Noonan syndrome Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.3445A>G(p.Met1149Val) in NF1 gene has been reported previously in heterozygous state in multiple individuals with neurofibromatosis (Koczkowska M, et al., 2020, Domingues S, et al., 2014 ). The Met1149 residue has been identified as a non-truncating hotspot in the gene with additional pathogenic variants that have been identified in patients with neurofibromatosis type 1 within two residues on each side of the variant (Koczkowska et al. 2020). Three other amino acid changes due to missense variants at the Met1149 residue that have been reported. The (p.Met1149Val) variant is reported with 0.0004% allele frequecny in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. Multiple lines of computational evidence (Polyphen- probably damaging, SIFT-damaging and Mutation Taster-disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Met at position 1149 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Met1149Val in NF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

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

Jul 03, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1149V pathogenic mutation (also known as c.3445A>G), located in coding exon 26 of the NF1 gene, results from an A to G substitution at nucleotide position 3445. The methionine at codon 1149 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in individuals with a confirmed or suspected clinical diagnosis of neurofibromatosis type 1, including in an individual in which it was identified as de novo (Domingues S et al. Case Rep Genet, 2014 Mar;2014:423071; Gengel N et al. Pediatr Rep, 2017 Jun;9:6810; Kang E et al. J Hum Genet, 2020 Jan;65:79-89; Srivastava P et al. Heliyon, 2024 Jan;10:e23685; Ambry internal data). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M;.
PhyloP100		8.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.96	D;B;.
Vest4		0.98
MutPred		0.66		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.87
MPC		1.1
ClinPred		0.90	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.56
gMVP		0.86
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1187097568; hg19: chr17-29559848; COSMIC: COSV100646550; COSMIC: COSV100646550;