chr1-77916107-A-C

Position:

chr1-77916107-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_144573.4(NEXN):c.1A>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000311 in 1,607,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

NEXN
NM_144573.4 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts 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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

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.1A>C	p.Met1?	start_lost	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.1A>C	p.Met1?	start_lost	2/13	1	NM_144573.4	ENSP00000333938	P3	Q0ZGT2-1
NEXN	ENST00000401035.7 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	2/9	1		ENSP00000383814
NEXN	ENST00000330010.12 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	2/12	2		ENSP00000327363	A1	Q0ZGT2-4
NEXN	ENST00000440324.5 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	2/10	5		ENSP00000411902

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

247520

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134284

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000873

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:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1455334

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000673

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2023

The p.M1? variant (also known as c.1A>C), located in coding exon 1 of the NEXN gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This amino acid position is highly conserved in available vertebrate species. Although biallelic loss of function alterations in NEXN have been associated with autosomal recessive NEXN-related cardiomyopathy, haploinsufficiency for NEXN has not been clearly established as a mechanism of disease for autosomal dominant NEXN-related cardiomyopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 01, 2022

This sequence change affects the initiator methionine of the NEXN mRNA. The next in-frame methionine is located at codon 38. This variant is present in population databases (rs749167943, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with NEXN-related conditions. ClinVar contains an entry for this variant (Variation ID: 519128). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

T;.;T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Benign

-0.57

MutationTaster

Benign

1.0

D;D;D;D

PROVEAN

Benign

-0.50

N;N;N;N

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.30

.;.;B;.

Vest4

0.90, 0.88

MutPred

1.0

Gain of catalytic residue at M1 (P = 0.1732);Gain of catalytic residue at M1 (P = 0.1732);Gain of catalytic residue at M1 (P = 0.1732);Gain of catalytic residue at M1 (P = 0.1732);

MVP

0.74

ClinPred

0.99

GERP RS

4.6

Varity_R

0.30

gMVP

0.092

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

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