Variant chr1-77916114-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144573.4(NEXN):c.8A>T(p.Asp3Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,455,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

NEXN
NM_144573.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 5.94

Variant links:

Genes affected

NEXN (HGNC:29557): (nexilin F-actin binding protein) This gene encodes a filamentous actin-binding protein that may function in cell adhesion and migration. Mutations in this gene have been associated with dilated cardiomyopathy, also known as CMD1CC. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

NEXN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXN	NM_144573.4 linkuse as main transcript	c.8A>T	p.Asp3Val	missense_variant	2/13	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12 linkuse as main transcript	c.8A>T	p.Asp3Val	missense_variant	2/13	1	NM_144573.4	ENSP00000333938	P3	Q0ZGT2-1
NEXN	ENST00000401035.7 linkuse as main transcript	c.8A>T	p.Asp3Val	missense_variant	2/9	1		ENSP00000383814
NEXN	ENST00000330010.12 linkuse as main transcript	c.8A>T	p.Asp3Val	missense_variant	2/12	2		ENSP00000327363	A1	Q0ZGT2-4
NEXN	ENST00000440324.5 linkuse as main transcript	c.8A>T	p.Asp3Val	missense_variant	2/10	5		ENSP00000411902

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1455446

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724110

show subpopulations

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:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2022

The p.D3V variant (also known as c.8A>T), located in coding exon 1 of the NEXN gene, results from an A to T substitution at nucleotide position 8. The aspartic acid at codon 3 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. 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. -

NEXN-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2023

The NEXN c.8A>T variant is predicted to result in the amino acid substitution p.Asp3Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

T;.;T;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T;D;D

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.51

D;D;D;D

MetaSVM

Uncertain

-0.051

MutationAssessor

Uncertain

2.4

.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.45

N;N;N;D

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Benign

0.14

T;D;D;D

Polyphen

1.0

.;.;D;.

Vest4

0.74, 0.89

MutPred

0.28

Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);

MVP

0.90

MPC

0.31

ClinPred

0.86

GERP RS

4.6

Varity_R

0.24

gMVP

0.46

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