rs4025981

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006393.3(NEBL):c.1051A>G(p.Met351Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0747 in 1,610,210 control chromosomes in the GnomAD database, including 5,193 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M351K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.058 ( 365 hom., cov: 32)

Exomes 𝑓: 0.076 ( 4828 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.85

Publications

22 publications found

Variant links:

Genes affected

NEBL (HGNC:16932): (nebulette) This gene encodes a nebulin like protein that is abundantly expressed in cardiac muscle. The encoded protein binds actin and interacts with thin filaments and Z-line associated proteins in striated muscle. This protein may be involved in cardiac myofibril assembly. A shorter isoform of this protein termed LIM nebulette is expressed in non-muscle cells and may function as a component of focal adhesion complexes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

NEBL Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NEBL links:

LOC102725112 (HGNC:):

LOC102725112 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016489923).

BP6

Variant 10-20850460-T-C is Benign according to our data. Variant chr10-20850460-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 45472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.079 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.1051A>G	p.Met351Val	missense_variant	Exon 11 of 28	ENST00000377122.9	NP_006384.1	O76041-1Q59FZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 link	c.1051A>G	p.Met351Val	missense_variant	Exon 11 of 28	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.0585

AC:

8904

AN:

152182

Hom.:

365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0531

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.0227

Gnomad SAS

AF:

0.0661

Gnomad FIN

AF:

0.0434

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0808

Gnomad OTH

AF:

0.0841

GnomAD2 exomes

AF:

0.0667

AC:

16766

AN:

251178

AF XY:

0.0702

show subpopulations

Gnomad AFR exome

AF:

0.0159

Gnomad AMR exome

AF:

0.0424

Gnomad ASJ exome

AF:

0.172

Gnomad EAS exome

AF:

0.0189

Gnomad FIN exome

AF:

0.0464

Gnomad NFE exome

AF:

0.0816

Gnomad OTH exome

AF:

0.0803

GnomAD4 exome

AF:

0.0764

AC:

111384

AN:

1457910

Hom.:

4828

Cov.:

AF XY:

0.0769

AC XY:

55795

AN XY:

725552

show subpopulations

African (AFR)

AF:

0.0180

AC:

601

AN:

33434

American (AMR)

AF:

0.0437

AC:

1952

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.174

AC:

4548

AN:

26072

East Asian (EAS)

AF:

0.0129

AC:

513

AN:

39666

South Asian (SAS)

AF:

0.0725

AC:

6246

AN:

86174

European-Finnish (FIN)

AF:

0.0474

AC:

2524

AN:

53304

Middle Eastern (MID)

AF:

0.174

AC:

999

AN:

5748

European-Non Finnish (NFE)

AF:

0.0802

AC:

88940

AN:

1108526

Other (OTH)

AF:

0.0840

AC:

5061

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

4628

9256

13884

18512

23140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0585

AC:

8906

AN:

152300

Hom.:

365

Cov.:

AF XY:

0.0570

AC XY:

4247

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0189

AC:

786

AN:

41572

American (AMR)

AF:

0.0531

AC:

812

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

656

AN:

3468

East Asian (EAS)

AF:

0.0230

AC:

119

AN:

5176

South Asian (SAS)

AF:

0.0662

AC:

319

AN:

4822

European-Finnish (FIN)

AF:

0.0434

AC:

461

AN:

10616

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0808

AC:

5498

AN:

68026

Other (OTH)

AF:

0.0833

AC:

176

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

435

870

1304

1739

2174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0770

Hom.:

1254

Bravo

AF:

0.0585

TwinsUK

AF:

0.0728

AC:

270

ALSPAC

AF:

0.0828

AC:

319

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.0834

AC:

717

ExAC

AF:

0.0650

AC:

7893

Asia WGS

AF:

0.0490

AC:

170

AN:

3478

EpiCase

AF:

0.0895

EpiControl

AF:

0.0955

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Met351Val in Exon 11 of NEBL: This variant is not expected to have clinical si gnificance because it has been identified in 8.3% (581/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs4025981). -

Jan 17, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

NEBL-related disorder

Benign:1

Nov 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary dilated cardiomyopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Sep 26, 2012

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.088

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.061

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.3

PhyloP100

1.9

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.094

Sift

Benign

0.091

Sift4G

Uncertain

0.031

Polyphen

0.017

Vest4

0.17

MPC

0.019

ClinPred

0.014

GERP RS

4.1

Varity_R

0.34

gMVP

0.20

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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rs4025981

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over