rs199474743

Variant names:

• chr17-31260403-A-G
• rs199474743
• NM_001042492.3:c.4465A>G

Your query was ambiguous. Multiple possible variants found:

• 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 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 the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.4465A>G	p.Ser1489Gly	missense_variant	Exon 34 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.4402A>G	p.Ser1468Gly	missense_variant	Exon 33 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.4465A>G	p.Ser1489Gly	missense_variant	Exon 34 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:9

Feb 03, 2021

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 09, 2025

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2018

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 17, 2022

Medical Genetics, University of Parma

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 17, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (PMID: 23913538, 25480383, 26056819); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25480383, 23913538, 26056819, 9668168, 9003501, 27838393, 15060124, 30245780, 34449562, 37751797, 22807134) -

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

Mar 09, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.
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;