rs1555614839

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP2

The NM_001042492.3(NF1):c.3245G>A(p.Gly1082Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000693 in 144,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1082V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 28)

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.49

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-31232120-G-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). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. GenCC has associacion of the gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.3245G>A	p.Gly1082Asp	missense_variant	25/58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.3245G>A	p.Gly1082Asp	missense_variant	25/57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.3245G>A	p.Gly1082Asp	missense_variant	25/58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.00000693

AC:

AN:

144342

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000716

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000693

AC:

AN:

144342

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69658

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000716

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 19, 2023

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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1082 of the NF1 protein (p.Gly1082Asp). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2023

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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25486365, 2121369) -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2023

The p.G1082D variant (also known as c.3245G>A), located in coding exon 25 of the NF1 gene, results from a G to A substitution at nucleotide position 3245. The glycine at codon 1082 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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

0.58

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.2

M;M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Uncertain

0.46

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.26

B;D;.

Vest4

0.84

MutPred

0.35

Loss of catalytic residue at A1081 (P = 0.0509);Loss of catalytic residue at A1081 (P = 0.0509);.;

MVP

0.84

MPC

0.91

ClinPred

0.97

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.66

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over