rs767247726

chr17-31223493-C-Gchr17-31223493-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001042492.3(NF1):c.1771C>G(p.Leu591Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.56

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NF1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1771C>G	p.Leu591Val	missense_variant	16/58	ENST00000358273.9
NF1	NM_000267.3	c.1771C>G	p.Leu591Val	missense_variant	16/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1771C>G	p.Leu591Val	missense_variant	16/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251086 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460350 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726528

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 14, 2022

ClinVar contains an entry for this variant (Variation ID: 404553). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is present in population databases (rs767247726, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 591 of the NF1 protein (p.Leu591Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Juvenile myelomonocytic leukemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 29, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2022

The p.L591V variant (also known as c.1771C>G), located in coding exon 16 of the NF1 gene, results from a C to G substitution at nucleotide position 1771. The leucine at codon 591 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	Benign	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	19
Dann	Benign	0.91
DEOGEN2	Benign	0.40	T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.0	N;N;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.0	N;N;N
REVEL	Benign	0.096
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.28
MutPred		0.16		Gain of catalytic residue at L591 (P = 0.1143);Gain of catalytic residue at L591 (P = 0.1143);.;
MVP		0.28
MPC		0.70
ClinPred		0.33	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs767247726; hg19: chr17-29550511;