rs115708584

chr10-20961672-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000417816.2(NEBL):c.357T>C(p.Asn119=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,602,118 control chromosomes in the GnomAD database, including 15 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (9 hom.)
• Consequence: NEBL ENST00000417816.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001460
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.75

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 10-20961672-A-G is Benign according to our data. Variant chr10-20961672-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 164773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20961672-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00654 (996/152240) while in subpopulation AFR AF= 0.0228 (948/41540). AF 95% confidence interval is 0.0216. There are 6 homozygotes in gnomad4. There are 484 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_001377322.1	c.357T>C	p.Asn119=	splice_region_variant, synonymous_variant	4/8
NEBL	NM_213569.2	c.357T>C	p.Asn119=	splice_region_variant, synonymous_variant	4/7
NEBL	NM_001377323.1	c.309T>C	p.Asn103=	splice_region_variant, synonymous_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000417816.2	c.357T>C	p.Asn119=	splice_region_variant, synonymous_variant	4/7	1		P1
NEBL	ENST00000674777.1	n.171T>C		non_coding_transcript_exon_variant	2/2
NEBL	ENST00000675114.1	n.565T>C		splice_region_variant, non_coding_transcript_exon_variant	6/9

Frequencies

GnomAD3 genomes AF: 0.00657 AC: 1000 AN: 152122 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

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: 0.000132

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00183 AC: 460 AN: 251106 Hom.: 1 AF XY: 0.00131 AC XY: 178 AN XY: 135698

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000658 AC: 954 AN: 1449878 Hom.: 9 Cov.: 28 AF XY: 0.000546 AC XY: 394 AN XY: 722160

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000200

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00654 AC: 996 AN: 152240 Hom.: 6 Cov.: 32 AF XY: 0.00650 AC XY: 484 AN XY: 74440

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000918 Hom.: 0

Bravo AF: 0.00763

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 19, 2012

p.Asn119Asn in Exon 04 of NEBL: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence and has been identified in 2.5% (94/3738) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs115708584). -

NEBL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.1
Dann	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.090		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: rs115708584; hg19: chr10-21250601;