rs41274310

chr18-34838086-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001386795.1(DTNA):c.1176-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,613,708 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (16 hom.)
• Consequence: DTNA NM_001386795.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.007986
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.48

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 18-34838086-T-C is Benign according to our data. Variant chr18-34838086-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 46430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-34838086-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 348 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTNA	NM_001386795.1	c.1176-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000444659.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTNA	ENST00000444659.6	c.1176-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001386795.1	P3

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00279 AC: 699 AN: 250878 Hom.: 3 AF XY: 0.00304 AC XY: 412 AN XY: 135568

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00504

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00330

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00346 AC: 5059 AN: 1461368 Hom.: 16 Cov.: 31 AF XY: 0.00358 AC XY: 2600 AN XY: 726970

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000582

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00516

Gnomad4 FIN exome AF: 0.000544

Gnomad4 NFE exome AF: 0.00349

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.00228 AC: 347 AN: 152340 Hom.: 2 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74498

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00347

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00373 Hom.: 0

Bravo AF: 0.00213

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00368

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2015	c.1086-8T>C in intron 12A of DTNA: This variant is not expected to have clinical significance because it has been identified in 0.5% (74/16144) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs41274310). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 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. -

Left ventricular noncompaction 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2020	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

DTNA: BS2 -

DTNA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
Cadd	Benign	16
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0080
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 8

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

Publications

LitVar

Other links and lift over

dbSNP: rs41274310; hg19: chr18-32418050;