rs149737043

Variant names:

• chr10-20852649-G-A
• rs149737043
• NM_006393.3:c.904C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-20852649-G-A
• chr10-20852649-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006393.3(NEBL):​c.904C>T​(p.Arg302*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,599,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NEBL NM_006393.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9148
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11
• Publications: 2 publications found

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

LOC102725112 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3	c.904C>T	p.Arg302*	stop_gained, splice_region_variant	Exon 10 of 28	ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9	c.904C>T	p.Arg302*	stop_gained, splice_region_variant	Exon 10 of 28	1	NM_006393.3	ENSP00000366326.4

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000481 AC: 12 AN: 249242 AF XY: 0.0000297

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000180 AC: 26 AN: 1447598 Hom.: 0 Cov.: 29 AF XY: 0.0000166 AC XY: 12 AN XY: 720956

African (AFR) AF: 0.00 AC: 0 AN: 33232

American (AMR) AF: 0.000269 AC: 12 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1099542

Other (OTH) AF: 0.0000167 AC: 1 AN: 59922

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74270

African (AFR) AF: 0.0000966 AC: 4 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000583 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Uncertain:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg302*) in the NEBL gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NEBL cause disease. This variant is present in population databases (rs149737043, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NEBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 580927). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Benign	0.69	D
PhyloP100		2.1
Vest4		0.93
GERP RS		5.3
Mutation Taster		=93/107	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Pathogenic	0.82
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

Other links and lift over

dbSNP: rs149737043; hg19: chr10-21141578; COSMIC: COSV65801441;