rs71534253

chr10-20852541-G-A

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.1008+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,608,718 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (11 hom.)
• Consequence: NEBL NM_006393.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00002403
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.470

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]

LOC102725112 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 10-20852541-G-A is Benign according to our data. Variant chr10-20852541-G-A is described in ClinVar as [Benign]. Clinvar id is 164757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20852541-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00495 (753/152254) while in subpopulation AFR AF= 0.0173 (717/41560). AF 95% confidence interval is 0.0162. There are 9 homozygotes in gnomad4. There are 366 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.1008+4C>T		splice_donor_region_variant, intron_variant		ENST00000377122.9
LOC102725112	XR_007062082.1	n.223+4015G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.1008+4C>T		splice_donor_region_variant, intron_variant		1	NM_006393.3

Frequencies

GnomAD3 genomes AF: 0.00491 AC: 747 AN: 152136 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000441

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00114 AC: 285 AN: 250176 Hom.: 2 AF XY: 0.000872 AC XY: 118 AN XY: 135330

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000548 AC: 798 AN: 1456464 Hom.: 11 Cov.: 31 AF XY: 0.000488 AC XY: 354 AN XY: 724936

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000722

Gnomad4 OTH exome AF: 0.000929

GnomAD4 genome AF: 0.00495 AC: 753 AN: 152254 Hom.: 9 Cov.: 32 AF XY: 0.00492 AC XY: 366 AN XY: 74440

Gnomad4 AFR AF: 0.0173

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00561

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	c.1008+4C>T in Intron 10 of NEBL: This variant is not expected to have clinical significance because it has been identified in 1.3% (48/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs71534253). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 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

Invitae

Dec 31, 2019

- -

NEBL-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.0010
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.018
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: rs71534253; hg19: chr10-21141470;