rs141707642

Positions:

• chr10-21173840-G-A
• chr10-21173840-G-C
• chr10-21173840-G-T

Variant summary

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

The NM_001377322.1(NEBL):​c.-7C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00647 in 1,610,848 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (89 hom.)
• Consequence: NEBL NM_001377322.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0820

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 10-21173840-G-A is Benign according to our data. Variant chr10-21173840-G-A is described in ClinVar as [Benign]. Clinvar id is 48638.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 = 0.0109 (1656/151970) while in subpopulation AFR AF= 0.0255 (1057/41506). AF 95% confidence interval is 0.0242. There are 14 homozygotes in gnomad4. There are 799 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_001377322.1	c.-7C>T		5_prime_UTR_premature_start_codon_gain_variant	1/8		NP_001364251.1
NEBL	NM_213569.2	c.-7C>T		5_prime_UTR_premature_start_codon_gain_variant	1/7		NP_998734.1
NEBL	NM_001377324.1	c.-165C>T		5_prime_UTR_premature_start_codon_gain_variant	1/7		NP_001364253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000417816.2	c.-7C>T		5_prime_UTR_premature_start_codon_gain_variant	1/7	1		ENSP00000393896.2
NEBL	ENST00000417816.2	c.-7C>T		5_prime_UTR_variant	1/7	1		ENSP00000393896.2
NEBL	ENST00000675747.1	n.54C>T		non_coding_transcript_exon_variant	1/28

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1655 AN: 151856 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.00520

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00461

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00714 AC: 1736 AN: 243110 Hom.: 22 AF XY: 0.00775 AC XY: 1029 AN XY: 132740

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0203

Gnomad FIN exome AF: 0.00373

Gnomad NFE exome AF: 0.00475

Gnomad OTH exome AF: 0.00517

GnomAD4 exome AF: 0.00601 AC: 8762 AN: 1458878 Hom.: 89 Cov.: 32 AF XY: 0.00642 AC XY: 4657 AN XY: 725812

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00261

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0219

Gnomad4 FIN exome AF: 0.00355

Gnomad4 NFE exome AF: 0.00467

Gnomad4 OTH exome AF: 0.00565

GnomAD4 genome AF: 0.0109 AC: 1656 AN: 151970 Hom.: 14 Cov.: 32 AF XY: 0.0108 AC XY: 799 AN XY: 74268

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0248

Gnomad4 FIN AF: 0.00520

Gnomad4 NFE AF: 0.00461

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.0112

EpiCase AF: 0.00496

EpiControl AF: 0.00409

ClinVar

Significance: 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

c.-7C>T in Exon 01 of NEBL: This variant is not expected to have clinical signif icance because it has been identified in 2.1% (79/3736) of African American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS; dbSNP rs141707642). -

NEBL-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.92

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: rs141707642; hg19: chr10-21462769;