rs199474743

Positions:

• chr17-31260403-A-G
• chr17-31260403-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.4465A>G​(p.Ser1489Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1489N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 8.69

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.

• 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31260403-A-G is Pathogenic according to our data. Variant chr17-31260403-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 68351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31260403-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.4465A>G	p.Ser1489Gly	missense_variant	34/58	ENST00000358273.9
NF1	NM_000267.3	c.4402A>G	p.Ser1468Gly	missense_variant	33/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.4465A>G	p.Ser1489Gly	missense_variant	34/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Nov 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Feb 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.55; 3Cnet: 0.92). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23913538, 25480383, 26056819, 27838393, 9003501). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1468 of the NF1 protein (p.Ser1468Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type 1 (NF1) (PMID: 9003501, 15060124, 23913538, 25480383, 26056819, 27838393; Invitae). ClinVar contains an entry for this variant (Variation ID: 68351). 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 not expected to disrupt NF1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Aug 17, 2022	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	Exonic splice variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Sabbagh 2013, Okumura 2015, Zhang 2015); Not observed in large population cohorts (Lek 2016); In silico analysis suggests this variant impacts gene splicing; This variant is associated with the following publications: (PMID: 30245780, 15060124, 23913538, 27838393, 9003501, 9668168, 26056819, 25480383) -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2023

The c.4402A>G variant (also known as p.S1468G), located in coding exon 33 of the NF1 gene, results from an A to G substitution at nucleotide position 4402. The serine at codon 1468 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in multiple individuals and families with clinical diagnoses of neurofibromatosis type 1 (NF1) and/or NF1-like phenotypes (Okumura A et al. Brain Dev., 2015 Aug;37:677-89; Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8; Zhang J et al. Sci Rep, 2015 Jun;5:11291). Functional analysis of RNA showed this alteration creates an aberrant splice acceptor site, and introduces a stop codon at amino acid position 1457 that results in a truncated NF1 protein (p.F1457*) (Okumura A et al. Brain Dev., 2015 Aug;37:677-89). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D;.;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.55	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0030	B;P;.
Vest4		0.86
MutPred		0.54		Gain of catalytic residue at S1489 (P = 0.0022);.;.;
MVP		0.95
MPC		1.6
ClinPred		0.88	D
GERP RS		6.0
Varity_R		0.30
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1
DS_AL_spliceai		0.90		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199474743; hg19: chr17-29587421;