chr17-31227526-T-A

Position:

• chr17-31227526-T-A

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.2329T>A​(p.Trp777Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W777G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.49

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 21 ACMG points.

• PS1: Transcript NM_001042492.3 (NF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a helix (size 21) in uniprot entity NF1_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) 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 chr17-31227526-T-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 17-31227526-T-A is Pathogenic according to our data. Variant chr17-31227526-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 230937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31227526-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2329T>A	p.Trp777Arg	missense_variant	20/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2329T>A	p.Trp777Arg	missense_variant	20/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2329T>A	p.Trp777Arg	missense_variant	20/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 16, 2024	- -
Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. ClinVar contains an entry for this variant (Variation ID: 230937). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 27322474, 34589056). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 777 of the NF1 protein (p.Trp777Arg). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 24, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31766501, 22034633, 16005615, 27322474, 23656349, 23913538, 17726231, 10712197, 25486365, 26582918) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2019

The p.W777R variant (also known as c.2329T>A), located in coding exon 20 of the NF1 gene, results from a T to A substitution at nucleotide position 2329. The tryptophan at codon 777 is replaced by arginine, an amino acid with dissimilar properties.The c.2329T>A and c.2329T>C alterations, both of which result in p.W777R, have been identified in several individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Cai Y et al. J. Dermatol. Sci. 2005 Aug; 39(2):125-7; Sabbagh A et al. Hum. Mutat. 2013 Nov; 34(11):1510-8; Evans DG et al. EBioMedicine, 2016 May;7:212-20, Ambry internal data). In addition, the c.2329T>A (p.W777R) alteration was determined to arise de novo in a patient with NF1; segregation studies showed both parents were negative for the alteration (Evans DG et al. EBioMedicine, 2016 May;7:212-20). Based on the available evidence, p.W777R is classified as a pathogenic mutation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2015

Thep.W777Rvariant (also known as c.2329T>A), located in coding exon 20 of theNF1gene, results from a T to A substitution at nucleotide position 2329. The tryptophan at codon 777 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in two families with clinical neurofibromatosis type 1 (NF1) and segregated with disease in the only family tested (Cai Y et al, J. Dermatol. Sci. 2005 Aug; 39(2):125-7; Sabbagh A et al, Hum. Mutat. 2013 Nov; 34(11):1510-8). In addition, different amino acid substitutions at codon 777 (p.W777G and p.W777S) have been detected in multiple NF1 families to date (Fahsold R et al, Am. J. Hum. Genet. 2000 Mar; 66(3):790-818; Bendova S et al, J. Mol. Neurosci. 2007; 31(3):273-9; van Minkelen R et al, Clin. Genet. 2014 Apr; 85(4):318-27). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFTin silico analyses, respectively. 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	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.72		Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);.;
MVP		0.91
MPC		2.3
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs876658853; hg19: chr17-29554544;