Genetic Variant NEBL:p.Asp467Glu (chr10-20835561-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006393.3(NEBL):c.1401C>A(p.Asp467Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.210

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006393.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEBL	NM_006393.3	MANE Select	c.1401C>A	p.Asp467Glu	missense	Exon 14 of 28	NP_006384.1
NEBL	NM_001377322.1		c.358-22621C>A		intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.358-22621C>A		intron	N/A	NP_998734.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEBL	ENST00000377122.9	TSL:1 MANE Select	c.1401C>A	p.Asp467Glu	missense	Exon 14 of 28	ENSP00000366326.4
NEBL	ENST00000417816.2	TSL:1	c.358-22621C>A		intron	N/A	ENSP00000393896.2
NEBL	ENST00000493005.5	TSL:1	n.1C>A		non_coding_transcript_exon	Exon 1 of 12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460488

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726642

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000383

AC:

AN:

52172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111894

Other (OTH)

AF:

0.00

AC:

AN:

60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

6.2

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.0072

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.60

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.77

PhyloP100

0.21

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.38

REVEL

Benign

0.14

Sift

Benign

0.50

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.63

MutPred

0.84

Loss of MoRF binding (P = 0.1371)

MVP

0.56

MPC

0.018

ClinPred

0.064

GERP RS

-0.86

Varity_R

0.034

gMVP

0.24

Mutation Taster

=92/8

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over