10-20888214-GAAA-GAA

Position:

• chr10-20888214-GAAA-GAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000377122.9(NEBL):​c.259-8del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,403,682 control chromosomes in the GnomAD database, including 44 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (21 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (23 hom.)
• Consequence: NEBL ENST00000377122.9 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.367

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 10-20888214-GA-G is Benign according to our data. Variant chr10-20888214-GA-G is described in ClinVar as [Benign]. Clinvar id is 179196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20888214-GA-G is described in Lovd as [Likely_benign]. Variant chr10-20888214-GA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0136 (1544/113452) while in subpopulation AFR AF= 0.0403 (1381/34234). AF 95% confidence interval is 0.0386. There are 21 homozygotes in gnomad4. There are 751 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3	c.259-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9	c.259-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006393.3	ENSP00000366326

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 1539 AN: 113342 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.0403

Gnomad AMI AF: 0.0290

Gnomad AMR AF: 0.00584

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000443

Gnomad SAS AF: 0.00176

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00114

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00256 AC: 546 AN: 213600 Hom.: 5 AF XY: 0.00201 AC XY: 233 AN XY: 115848

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000192

Gnomad SAS exome AF: 0.00136

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000759

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.00162 AC: 2096 AN: 1290230 Hom.: 23 Cov.: 23 AF XY: 0.00153 AC XY: 989 AN XY: 646474

Gnomad4 AFR exome AF: 0.0324

Gnomad4 AMR exome AF: 0.00361

Gnomad4 ASJ exome AF: 0.0000417

Gnomad4 EAS exome AF: 0.000350

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.0000794

Gnomad4 NFE exome AF: 0.000739

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.0136 AC: 1544 AN: 113452 Hom.: 21 Cov.: 31 AF XY: 0.0137 AC XY: 751 AN XY: 54638

Gnomad4 AFR AF: 0.0403

Gnomad4 AMR AF: 0.00583

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000444

Gnomad4 SAS AF: 0.00177

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00114

Gnomad4 OTH AF: 0.0123

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 02, 2015	259-8delT in intron 3 of NEBL: This variant is located outside the conserved +/- 1, 2 region of the splicing consensus sequence, is part of a polyT stretch, and does not alter the sequence of the ROI. It has been identified in 3% (309/9414) of African Chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org/; dbSNP rs71578979). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 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. -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs57918610; hg19: chr10-21177143;