rs71578938

chr10-20845374-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006393.3(NEBL):c.1117-6T>G 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 0.00131 in 1,469,078 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (6 hom.)
• Consequence: NEBL NM_006393.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.3635
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.90

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 10-20845374-A-C is Benign according to our data. Variant chr10-20845374-A-C is described in ClinVar as [Benign]. Clinvar id is 45474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00494 (753/152286) while in subpopulation AFR AF= 0.0164 (680/41560). AF 95% confidence interval is 0.0153. There are 8 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.1117-6T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.1117-6T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006393.3

Frequencies

GnomAD3 genomes AF: 0.00492 AC: 748 AN: 152166 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

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: 0.000485

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00154 AC: 385 AN: 249592 Hom.: 1 AF XY: 0.00126 AC XY: 170 AN XY: 134976

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000622

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000532

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000889 AC: 1171 AN: 1316792 Hom.: 6 Cov.: 22 AF XY: 0.000833 AC XY: 552 AN XY: 662748

Gnomad4 AFR exome AF: 0.0187

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.000160

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000564

Gnomad4 FIN exome AF: 0.0000947

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00494 AC: 753 AN: 152286 Hom.: 8 Cov.: 32 AF XY: 0.00486 AC XY: 362 AN XY: 74482

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00233 Hom.: 0

Bravo AF: 0.00549

Asia WGS AF: 0.00376 AC: 13 AN: 3476

EpiCase AF: 0.000764

EpiControl AF: 0.000891

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Apr 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	c.1117-6T>G in Intron 11 of NEBL: This variant is not expected to have clinical significance because it has been identified in 2.2% (82/3734) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs71578938). -

NEBL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	15
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.36
dbscSNV1_RF	Benign	0.56
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: rs71578938; hg19: chr10-21134303;