Variant chr10-20888207-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006393.3(NEBL):c.259G>A(p.Ala87Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NEBL
NM_006393.3 missense, splice_region

Scores

Splicing: ADA: 0.001936

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059872895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3 link	c.259G>A	p.Ala87Thr	missense_variant, splice_region_variant	4/28	ENST00000377122.9	NP_006384.1	O76041-1Q59FZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 link	c.259G>A	p.Ala87Thr	missense_variant, splice_region_variant	4/28	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000420

AC:

AN:

238274

Hom.:

AF XY:

0.00

AC XY:

AN XY:

128672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000911

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.98e-7

AC:

AN:

1432560

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714028

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:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 11, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NEBL-related disease. This variant is present in population databases (rs368856187, ExAC 0.002%). This sequence change replaces alanine with threonine at codon 87 of the NEBL protein (p.Ala87Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.28

DEOGEN2

Benign

0.010

T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.060

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

N;.

PrimateAI

Benign

0.47

PROVEAN

Benign

0.070

N;N

REVEL

Benign

0.014

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;.

Polyphen

0.0

B;.

Vest4

0.16

MVP

0.32

MPC

0.016

ClinPred

0.15

GERP RS

2.9

Varity_R

0.054

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0019

dbscSNV1_RF

Benign

0.22

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