18-34875229-G-T

Position:

• chr18-34875229-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001386795.1(DTNA):​c.1744-10G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,613,302 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (5 hom.)
• Consequence: DTNA NM_001386795.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9654
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.69

Genes affected

DTNA (HGNC:3057): (dystrobrevin alpha) The protein encoded by this gene belongs to the dystrobrevin subfamily of the dystrophin family. This protein is a component of the dystrophin-associated protein complex (DPC), which consists of dystrophin and several integral and peripheral membrane proteins, including dystroglycans, sarcoglycans, syntrophins and alpha- and beta-dystrobrevin. The DPC localizes to the sarcolemma and its disruption is associated with various forms of muscular dystrophy. Mutations in this gene are associated with left ventricular noncompaction with congenital heart defects. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 18-34875229-G-T is Benign according to our data. Variant chr18-34875229-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 46417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-34875229-G-T is described in Lovd as [Likely_benign]. Variant chr18-34875229-G-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 324 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTNA	NM_001386795.1	c.1744-10G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6	c.1744-10G>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001386795.1	ENSP00000405819	P3

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152136 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00387

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00191 AC: 479 AN: 251042 Hom.: 3 AF XY: 0.00192 AC XY: 261 AN XY: 135722

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00225 AC: 3289 AN: 1461048 Hom.: 5 Cov.: 31 AF XY: 0.00219 AC XY: 1595 AN XY: 726718

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00674

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00403

Gnomad4 NFE exome AF: 0.00241

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00213 AC: 324 AN: 152254 Hom.: 2 Cov.: 33 AF XY: 0.00218 AC XY: 162 AN XY: 74436

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00387

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00223 Hom.: 1

Bravo AF: 0.00220

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Left ventricular noncompaction 1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 04, 2016	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 03, 2012	c.1492-10G>T in intron 16 of DTNA: This variant is not expected to have clinical significance because it has been identified in 0.3% (173/66336) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg/; dbSNP rs192561043). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

DTNA-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.68

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs192561043; hg19: chr18-32455193;