rs1555618656

chr17-31259069-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_001042492.3(NF1):c.4370A>G(p.Lys1457Arg) 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. K1457E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.67

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 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain 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 chr17-31259068-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 237563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, NF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8
• PP5: Variant 17-31259069-A-G is Pathogenic according to our data. Variant chr17-31259069-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 484060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.4370A>G	p.Lys1457Arg	missense_variant	33/58	ENST00000358273.9
NF1	NM_000267.3	c.4307A>G	p.Lys1436Arg	missense_variant	32/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.4370A>G	p.Lys1457Arg	missense_variant	33/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1452406 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1436 of the NF1 protein (p.Lys1436Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 484060). 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. Experimental studies have shown that this missense change affects NF1 function (PMID: 8628317, 12787671). This variant disrupts the p.Lys1436 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21354044, 23913538, 24789688). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2018

The p.K1436R variant (also known as c.4307A>G), located in coding exon 32 of the NF1 gene, results from an A to G substitution at nucleotide position 4307. The lysine at codon 1436 is replaced by arginine, an amino acid with highly similar properties. Functional studies have shown this variant to have altered binding affinity and significant reduction in catalytic activity (Ahmadian MR et al. J. Mol. Biol. 2003 Jun;329:699-710). Based on internal structural analysis, this variant is anticipated to result in disruption of a known structural motif (Scheffzek K et al. EMBO J. 1998 Aug;17:4313-27). While this exact alteration has not been previously reported, two other alterations at the same codon (p.K1436E and p.K1436Q) have been reported in individuals diagnosed with NF1 (Thomas L et al. Hum. Mutat. 2012 Dec;33:1687-96; Valero MC et al. J Mol Diagn. 2011 Mar;13:113-22; Sabbagh A et al. Hum. Mutat. 2013 Nov;34:1510-8). 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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.10	T;T;T
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.91
MutPred		0.43		Loss of methylation at K1457 (P = 0.0125);.;.;
MVP		0.97
MPC		0.63
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.85
gMVP		0.76

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: rs1555618656; hg19: chr17-29586087;