17-31350205-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001042492.3(NF1):c.7344A>T(p.Glu2448Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,688 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2448G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.251

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neurofibromatosis type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
Moyamoya disease
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 27 uncertain in NM_001042492.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32054776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.7344A>T	p.Glu2448Asp	missense_variant	Exon 50 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4 link	c.7281A>T	p.Glu2427Asp	missense_variant	Exon 49 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.7344A>T	p.Glu2448Asp	missense_variant	Exon 50 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727138

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111882

Other (OTH)

AF:

0.00

AC:

AN:

60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 2427 of the NF1 protein (p.Glu2427Asp). 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. 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 with a negative predictive value of 95%. 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.

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E2427D variant (also known as c.7281A>T), located in coding exon 49 of the NF1 gene, results from an A to T substitution at nucleotide position 7281. The glutamic acid at codon 2427 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

2.0

M;.;.

PhyloP100

0.25

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.21

T;T;T

Vest4

0.81

ClinPred

0.93

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.41

Mutation Taster

=40/60

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over