NM_006393.3:c.2997A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006393.3(NEBL):c.2997A>G(p.Thr999Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 1,613,892 control chromosomes in the GnomAD database, including 5,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.086 ( 635 hom., cov: 32)

Exomes 𝑓: 0.076 ( 4674 hom. )

Consequence

NEBL
NM_006393.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.181

Publications

14 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 10-20785795-T-C is Benign according to our data. Variant chr10-20785795-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 45497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.181 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.2997A>G	p.Thr999Thr	synonymous_variant	Exon 28 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.2997A>G	p.Thr999Thr	synonymous_variant	Exon 28 of 28	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.0856

AC:

13018

AN:

152124

Hom.:

634

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.0922

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.0543

Gnomad FIN

AF:

0.0524

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0746

Gnomad OTH

AF:

0.0722

GnomAD2 exomes

AF:

0.0800

AC:

20073

AN:

250986

AF XY:

0.0756

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.156

Gnomad ASJ exome

AF:

0.0946

Gnomad EAS exome

AF:

0.000708

Gnomad FIN exome

AF:

0.0544

Gnomad NFE exome

AF:

0.0730

Gnomad OTH exome

AF:

0.0808

GnomAD4 exome

AF:

0.0756

AC:

110490

AN:

1461650

Hom.:

4674

Cov.:

AF XY:

0.0746

AC XY:

54248

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.120

AC:

3999

AN:

33462

American (AMR)

AF:

0.148

AC:

6608

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0960

AC:

2509

AN:

26130

East Asian (EAS)

AF:

0.00176

AC:

AN:

39682

South Asian (SAS)

AF:

0.0587

AC:

5063

AN:

86258

European-Finnish (FIN)

AF:

0.0539

AC:

2880

AN:

53410

Middle Eastern (MID)

AF:

0.0830

AC:

478

AN:

5762

European-Non Finnish (NFE)

AF:

0.0756

AC:

84093

AN:

1111858

Other (OTH)

AF:

0.0793

AC:

4790

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

5721

11441

17162

22882

28603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0855

AC:

13017

AN:

152242

Hom.:

635

Cov.:

AF XY:

0.0845

AC XY:

6286

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.119

AC:

4921

AN:

41518

American (AMR)

AF:

0.109

AC:

1664

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0922

AC:

320

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0541

AC:

261

AN:

4820

European-Finnish (FIN)

AF:

0.0524

AC:

557

AN:

10624

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0746

AC:

5072

AN:

68010

Other (OTH)

AF:

0.0710

AC:

150

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

608

1217

1825

2434

3042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0894

Hom.:

693

Bravo

AF:

0.0923

Asia WGS

AF:

0.0330

AC:

116

AN:

3478

EpiCase

AF:

0.0761

EpiControl

AF:

0.0759

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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.Thr999Thr in Exon 28 of NEBL: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence and has been identified in 12.4% (462/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs2296614). -

Apr 10, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

May 17, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

1.1

(source)

DANN

Benign

0.59

PhyloP100

0.18

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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NM_006393.3:c.2997A>G

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