ENST00000417816.2:c.-7C>T

Variant names:

• chr10-21173840-G-A
• rs141707642
• ENST00000417816.2:c.-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000417816.2(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 ENST00000417816.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0820
• Publications: 0 publications found

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-AS1 (HGNC:44899): (NEBL antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1656 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000417816.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	NM_001377322.1		c.-7C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001364251.1
	NEBL	NM_213569.2		c.-7C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_998734.1
	NEBL	NM_001377324.1		c.-165C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001364253.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000417816.2	TSL:1	c.-7C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000393896.2
	NEBL	ENST00000417816.2	TSL:1	c.-7C>T		5_prime_UTR	Exon 1 of 7	ENSP00000393896.2
	NEBL	ENST00000675747.1		n.54C>T		non_coding_transcript_exon	Exon 1 of 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

GnomAD2 exomes AF: 0.00714 AC: 1736 AN: 243110 AF XY: 0.00775

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 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

African (AFR) AF: 0.0278 AC: 930 AN: 33426

American (AMR) AF: 0.00264 AC: 118 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00261 AC: 68 AN: 26082

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39614

South Asian (SAS) AF: 0.0219 AC: 1885 AN: 86192

European-Finnish (FIN) AF: 0.00355 AC: 182 AN: 51260

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.00467 AC: 5190 AN: 1111538

Other (OTH) AF: 0.00565 AC: 341 AN: 60322

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

African (AFR) AF: 0.0255 AC: 1057 AN: 41506

American (AMR) AF: 0.00379 AC: 58 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5068

South Asian (SAS) AF: 0.0248 AC: 119 AN: 4808

European-Finnish (FIN) AF: 0.00520 AC: 55 AN: 10584

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00461 AC: 313 AN: 67932

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00354 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

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		0.082
PromoterAI		-0.0086	Neutral
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs141707642; hg19: chr10-21462769;