rs4025981

Positions:

chr10-20850460-T-C

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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:6

Conservation

PhyloP100: 1.85

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 links:

LOC102725112 (HGNC:):

LOC102725112 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	UniProt
NEBL	NM_006393.3 linkuse as main transcript	c.1051A>G	p.Met351Val	missense_variant	11/28	ENST00000377122.9
LOC102725112	XR_007062082.1 linkuse as main transcript	n.223+1934T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9 linkuse as main transcript	c.1051A>G	p.Met351Val	missense_variant	11/28	1	NM_006393.3		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

GnomAD3 exomes

AF:

0.0667

AC:

16766

AN:

251178

Hom.:

705

AF XY:

0.0702

AC XY:

9528

AN XY:

135754

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 SAS exome

AF:

0.0720

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

Gnomad4 AFR exome

AF:

0.0180

Gnomad4 AMR exome

AF:

0.0437

Gnomad4 ASJ exome

AF:

0.174

Gnomad4 EAS exome

AF:

0.0129

Gnomad4 SAS exome

AF:

0.0725

Gnomad4 FIN exome

AF:

0.0474

Gnomad4 NFE exome

AF:

0.0802

Gnomad4 OTH exome

AF:

0.0840

GnomAD4 genome

AF:

0.0585

AC:

8906

AN:

152300

Hom.:

365

Cov.:

AF XY:

0.0570

AC XY:

4247

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0189

Gnomad4 AMR

AF:

0.0531

Gnomad4 ASJ

AF:

0.189

Gnomad4 EAS

AF:

0.0230

Gnomad4 SAS

AF:

0.0662

Gnomad4 FIN

AF:

0.0434

Gnomad4 NFE

AF:

0.0808

Gnomad4 OTH

AF:

0.0833

Alfa

AF:

0.0821

Hom.:

968

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	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). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2014	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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 2019

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). -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2012

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

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

MutationTaster

Benign

1.0

D;D;N

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

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

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