chr17-31214554-T-G

Position:

• chr17-31214554-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001042492.3(NF1):​c.1496T>G​(p.Leu499Arg) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L499P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 7.47

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 10 ACMG points.

• PM1: In a helix (size 19) in uniprot entity NF1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31214554-T-C 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, 0.873
• PP5: Variant 17-31214554-T-G is Pathogenic according to our data. Variant chr17-31214554-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547592.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=4}. Variant chr17-31214554-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.1496T>G	p.Leu499Arg	missense_variant	13/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1496T>G	p.Leu499Arg	missense_variant	13/57		NP_000258.1
NF1	NM_001128147.3	c.1496T>G	p.Leu499Arg	missense_variant	13/15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1496T>G	p.Leu499Arg	missense_variant	13/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	NHS Central & South Genomic Laboratory Hub	Nov 11, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 29, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu499 amino acid residue in NF1. Other variant(s) that disrupt this residue have been observed in individuals with NF1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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: 547592). This missense change has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 26740943, 28529006). It has also been observed to segregate with disease in related individuals. 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 499 of the NF1 protein (p.Leu499Arg). -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The p.L499R variant (also known as c.1496T>G), located in coding exon 13 of the NF1 gene, results from a T to G substitution at nucleotide position 1496. The leucine at codon 499 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in an individual with NF1 or clinical suspicion of NF1 (Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25; Paulo P et al. J Mol Diagn, 2017 07;19:502-513). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.4	M;M;M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.5	.;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.98, 0.97
MutPred		0.63		Gain of MoRF binding (P = 0.0098);Gain of MoRF binding (P = 0.0098);Gain of MoRF binding (P = 0.0098);Gain of MoRF binding (P = 0.0098);.;
MVP		0.88
MPC		2.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.98

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: rs1555612288; hg19: chr17-29541572;