17-31336380-T-G

Position:

• chr17-31336380-T-G

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.6054T>G​(p.Ser2018Arg) variant causes a missense change involving the alteration of a non-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 (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.93

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 (HGNC:):

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: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 17-31336380-T-G is Pathogenic according to our data. Variant chr17-31336380-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 527592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.6054T>G	p.Ser2018Arg	missense_variant	41/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.5991T>G	p.Ser1997Arg	missense_variant	40/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.6054T>G	p.Ser2018Arg	missense_variant	41/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NF1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The NF1 c.6054T>G variant is predicted to result in the amino acid substitution p.Ser2018Arg. This variant is also referred to as c.5991T>G (p.Ser1997Arg) in alternate transcript (NM_000267). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. A different nucleotide variant that results in the same amino acid substitution, c.6052A>C (p.Ser2018Arg), has been reported in an individual with neurofibromatosis type 1 (Tsipi et al. 2018. PubMed ID: 30308447). Additionally, an in vitro functional study expressing the p.Ser2018Arg variant in HEK293 cells demonstrated neurofibromin protein levels similar to wildtype (~91%), but an increase in Ras signaling from increased GTP‐Ras and pERK/ERK levels (Long et al. 2021. PubMed ID: 34694046). Different missense variants impacting the same amino acid (p.Ser2018Gly and p.Ser2018Ile) have also been reported in individuals with NF1-related syndromes (de novo, Lopez et al 2019. PubMed ID: 29368848; Table S4, Paulo et al. 2017. PubMed ID: 28529006), suggesting the p.Ser2018 residue is important for NF1 function. The c.60554T>G (p.Ser2018Arg) variant is interpreted as likely pathogenic. -

Neurofibromatosis, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NF1 function (PMID: 34694046). 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: 527592). This missense change has been observed in individual(s) with neurofibromatosis type I (PMID: 34694046). 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 serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1997 of the NF1 protein (p.Ser1997Arg). -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

The c.5991T>G (p.S1997R) alteration is located in exon 40 (coding exon 40) of the NF1 gene. This alteration results from a T to G substitution at nucleotide position 5991, causing the serine (S) at amino acid position 1997 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Four alterations at the same codon, c.5989A>C (p.S1997R), c.5989A>G (p.S1997G), c.5990G>T (p.S1997I), and c.5990G>A (p.S1997N), have been observed in multiple individuals with features consistent with neurofibromatosis type 1 and reported to be the result of a de novo mutation in at least one individual (Paulo, 2017; Tsipi, 2018; Lopez, 2019; Bianchessi, 2020; Ambry internal data; external communication). 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). Functional studies showed abnormal function in an overexpression assay involving mouse NF1 with p.S1997R in HEK293 cells; however, the physiological relevance of this finding is unclear (Long, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	2.9	M;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	D;D;D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0050	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		0.99	D;D;.;.
Vest4		0.96
MutPred		0.57		Gain of solvent accessibility (P = 0.0171);.;.;.;
MVP		0.99
MPC		2.4
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.73
gMVP		1.0

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: rs1555534600; hg19: chr17-29663398;