rs1555618528

Positions:

• chr17-31258426-T-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.4256T>A​(p.Val1419Asp) 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. 12/21 in silico tools predict a damaging 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. V1419A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.64

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 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.976
• PP5: Variant 17-31258426-T-A is Pathogenic according to our data. Variant chr17-31258426-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 527578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.4256T>A	p.Val1419Asp	missense_variant	32/58	ENST00000358273.9
NF1	NM_000267.3	c.4193T>A	p.Val1398Asp	missense_variant	31/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.4256T>A	p.Val1419Asp	missense_variant	32/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The NF1 c.4256T>A variant has been reported in individual affected with neurofibromatosis type I (Thomas et. al., 2012). 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 laboratory indicates that this missense variant is expected to disrupt NF1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. The p.Val1419Asp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic. The amino acid change p.Val1419Asp in NF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 1419 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2019	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported in several individuals affected with neurofibromatosis type I (PMID: 22807134, Invitae). ClinVar contains an entry for this variant (Variation ID: 527578). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with aspartic acid at codon 1398 of the NF1 protein (p.Val1398Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.3	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.99
MutPred		0.86		Gain of disorder (P = 0.0397);.;.;
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.98
gMVP		0.94

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: rs1555618528; hg19: chr17-29585444;