17-31233092-T-G

Position:

• chr17-31233092-T-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.3587T>G​(p.Leu1196Arg) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. L1196F) 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:4 O:1
• 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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31233091-C-T 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, 0.896
• PP5: Variant 17-31233092-T-G is Pathogenic according to our data. Variant chr17-31233092-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31233092-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3587T>G	p.Leu1196Arg	missense_variant	27/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3587T>G	p.Leu1196Arg	missense_variant	27/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3587T>G	p.Leu1196Arg	missense_variant	27/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no reduced RAS GAP activity or NF-SPRED1 co-immunoprecipitation (Douben H et al. 2023. Hindawi Human Mutation. https://onlinelibrary.wiley.com/doi/10.1155/2023/9628049); This variant is associated with the following publications: (PMID: 24803665, 22664660, 23047742, 27838393, 26740943, 19845691, 15060124, 17103458, 25486365, 2121369, 22807134, 35121649, Douben2023[Functional study]) -

NF1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2023

The NF1 c.3587T>G variant is predicted to result in the amino acid substitution p.Leu1196Arg. This variant was reported in an individual with neurofibromatosis type 1 (Mattocks et al. 2004. PubMed ID: 15060124). Additionally, different missense variants affecting this amino acid (p.Leu1196Val, p.Leu1196Phe) have been reported in individuals with neurofibromatosis type 1 (Table S2 - Bianchessi et al. 2015. PubMed ID: 26740943; Table S3 - Kang et al. 2020. PubMed ID: 31776437). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Neurofibromatosis, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 06, 2023

ClinVar contains an entry for this variant (Variation ID: 68336). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu1196 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15060124, 17103458, 22664660, 23047742, 27838393). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with clinical features of neurofibromatosis and/or NF1-Noonan syndrome (PMID: 17103458; Invitae). 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 leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1196 of the NF1 protein (p.Leu1196Arg). -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2019

The p.L1196R variant (also known as c.3587T>G), located in coding exon 27 of the NF1 gene, results from a T to G substitution at nucleotide position 3587. The leucine at codon 1196 is replaced by arginine, an amino acid with dissimilar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual meeting NIH diagnostic criteria for neurofibromatosis type 1 (NF1). In addition, this alteration has been identified in two individuals with features of NF1 (Mattocks C et al. J. Med. Genet., 2004 Apr;41:e48; Hüffmeier U et al. Am. J. Med. Genet. A, 2006 Dec;140:2749-56). A different alteration located at the same position, p.L1196F, has been detected twice: once as a de novo occurrence in an individual with a clinical diagnosis of Noonan syndrome who had cafe au lait spots (Croonen EA et al. Clin. Dysmorphol., 2012 Oct;21:212-4) and second, in an individual with either a suspected or confirmed diagnosis of NF1 (Calì F et al. Eur. J. Med. Genet. 2017 Feb;60:93-99). Additionally, another alteration located at the same position, p.L1196V, was detected once in a cohort of individuals with NF1 features (Bianchessi D et al. Mol. Genet. Genomic Med. 2015 Nov;3:513-25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.0011	D
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.24	B;P;.
Vest4		0.95
MutPred		0.66		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);.;
MVP		0.93
MPC		2.1
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.86
gMVP		0.95

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: rs199474741; hg19: chr17-29560110; COSMIC: COSV62199881;