chr17-31334879-T-C

Variant names:

• chr17-31334879-T-C
• rs199474791
• NM_001042492.3:c.5854T>C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.5854T>C​(p.Trp1952Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,812 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1952C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • 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:5 O:1
• Conservation: PhyloP100: 7.51
• Publications: 9 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 22 ACMG points.

• PS1: Transcript NM_001042492.3 (NF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 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 chr17-31334881-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3572040.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-31334879-T-C is Pathogenic according to our data. Variant chr17-31334879-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68357.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.5854T>C	p.Trp1952Arg	missense_variant	Exon 40 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.5791T>C	p.Trp1931Arg	missense_variant	Exon 39 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5854T>C	p.Trp1952Arg	missense_variant	Exon 40 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727204

⚠️ 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: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

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

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.5854T>C (p.Trp1952Arg) variant in the NF1 gene has been reported has been observed in individuals with neurofibromatosis type 1 (Mao B et al., 2018). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Tryptophan at position 1952 is changed to a Arginie changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Trp1952Arg in NF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. Functional studies are further required to prove the variant's pathogenicity. For these reasons, this variant has been classified as Likely Pathogenic. -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1931 of the NF1 protein (p.Trp1931Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 9101300, 16944272, 17311297, 23244495, 29914388). ClinVar contains an entry for this variant (Variation ID: 68357). 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%. For these reasons, this variant has been classified as Pathogenic. -

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

Aug 07, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5791T>C (p.W1931R) alteration is located in exon 39 (coding exon 39) of the NF1 gene. This alteration results from a T to C substitution at nucleotide position 5791, causing the tryptophan (W) at amino acid position 1931 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, also designated c.5854T>C (p.W1952R), has been detected in numerous individuals meeting NIH criteria for a clinical diagnosis of neurofibromatosis type 1 (Mao, 2018; Hudson, 1997; Griffiths, 2007; Calì, 2017; Alkindy, 2012). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 28, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W1952R variant (also known as c.5854T>C), located in coding exon 40 of the NF1 gene, results from a T to C substitution at nucleotide position 5854. The tryptophan at codon 1952 is replaced by arginine, an amino acid with dissimilar properties. In one study, this variant segregated with disease in a proband and her affected son, and was not seen in her three unaffected children (<span style="font-size:13.3333339691162px">Hudson J, Hum. Mutat. 1997 ; 9(4):366-7). In addition, this alteration has been detected in multiple unrelated individuals meeting NIH <span style="font-size:13.3333px">diagnostic<span style="font-size:13.3333px"> criteria for NF1 (Griffiths S, Fam. Cancer 2007; 6(1):21-34; Cal&igrave;<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px"> F et al. Eur J Med Genet<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px">, 2017 Feb;60:93-99; Alkindy<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px"> A et al. Hum. Genomics<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px">, 2012 Aug;6:12). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-12	D;D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		1.0
MutPred		0.90		Gain of sheet (P = 0.0101);.;.;.;
MVP		0.99
MPC		3.1
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.98
Mutation Taster		=0/100	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: rs199474791; hg19: chr17-29661897;