rs1131691103

chr17-31327541-A-Gchr17-31327541-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_001042492.3(NF1):c.5311A>G(p.Lys1771Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.44

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a strand (size 2) in uniprot entity NF1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NF1
• PP5: Variant 17-31327541-A-G is Pathogenic according to our data. Variant chr17-31327541-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31327541-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.5311A>G	p.Lys1771Glu	missense_variant	38/58	ENST00000358273.9
NF1	NM_000267.3	c.5248A>G	p.Lys1750Glu	missense_variant	37/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.5311A>G	p.Lys1771Glu	missense_variant	38/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1750 of the NF1 protein (p.Lys1750Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 and neurofibromatosis-Noonan syndrome (PMID: 23656349; Invitae; externalcommunication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 428982). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 08, 2022

This variant has been reported in the literature as de novo in one individual with a clinical diagnosis or suspicion of Neurofibromatosis 1 (van Minkelen 2014 PMID:23656349). This variant has also been identified by multiple laboratories in several individuals with features suggestive of or consistent with Neurofibromatosis 1, and was determined to be de novo in at least one individual (ClinVar Variation ID:428982; inter-laboratory communications). Additionally, this variant is absent from large control databases. In summary, this variant is classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2023

Not observed in large population cohorts (gnomAD); 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: 23656349) -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2022

The p.K1750E variant (also known as c.5248A>G), located in coding exon 37 of the NF1 gene, results from an A to G substitution at nucleotide position 5248. The lysine at codon 1750 is replaced by glutamic acid, an amino acid with similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with NF1-related features tested in our laboratory. This variant has been reported as de novo in one individual from a cohort of patients with a clinical diagnosis or symptoms of NF1 (van Minkelen R et al. Clin. Genet. 2014 Apr;85:318-27). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2016

The p.K1771E variant (also known as c.5311A>G, c.5248A>G and p.K1750E), located in coding exon 38 of the NF1 gene, results from an A to G substitution at nucleotide position 5311. The lysine at codon 1771 is replaced by glutamic acid, an amino acid with similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with NF1-related features tested in our laboratory. This variant has been reported as de novo in one individual from a cohort of patients with a clinical diagnosis or symptoms of NF1 (van Minkelen R et al. Clin. Genet., 2014 Apr;85:318-27). In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;T
Eigen	Benign	0.032
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	0.92	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.0060	B;B;.
Vest4		0.41
MutPred		0.41		Loss of methylation at K1771 (P = 0.0068);.;.;
MVP		0.77
MPC		1.5
ClinPred		0.83	D
GERP RS		6.0
Varity_R		0.84
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131691103; hg19: chr17-29654559; COSMIC: COSV62217301; COSMIC: COSV62217301;