rs139872140

Variant names:

• chr18-34838788-C-T
• rs139872140
• NM_001386795.1:c.1297C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001386795.1(DTNA):​c.1297C>T​(p.His433Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00228 in 1,613,756 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: DTNA NM_001386795.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 7.15
• Publications: 8 publications found

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]

DTNA Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• left ventricular noncompaction 1

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Meniere disease

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06422153).
• BP6: Variant 18-34838788-C-T is Benign according to our data. Variant chr18-34838788-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46431.
• BS2: High AC in GnomAd4 at 309 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386795.1. 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
	DTNA	NM_001386795.1	MANE Select	c.1297C>T	p.His433Tyr	missense	Exon 13 of 23	NP_001373724.1
	DTNA	NM_001386788.1		c.1297C>T	p.His433Tyr	missense	Exon 13 of 23	NP_001373717.1
	DTNA	NM_001390.5		c.1216C>T	p.His406Tyr	missense	Exon 12 of 22	NP_001381.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNA	ENST00000444659.6	TSL:5 MANE Select	c.1297C>T	p.His433Tyr	missense	Exon 13 of 23	ENSP00000405819.2
	DTNA	ENST00000348997.9	TSL:1	c.1207C>T	p.His403Tyr	missense	Exon 12 of 17	ENSP00000336682.4
	DTNA	ENST00000598334.5	TSL:1	c.1086-9508C>T		intron	N/A	ENSP00000470152.1

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 309 AN: 152102 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00695

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00143 AC: 360 AN: 251370 AF XY: 0.00146

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00231 AC: 3372 AN: 1461536 Hom.: 6 Cov.: 31 AF XY: 0.00219 AC XY: 1589 AN XY: 727064

African (AFR) AF: 0.000269 AC: 9 AN: 33452

American (AMR) AF: 0.00215 AC: 96 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00272 AC: 3025 AN: 1111776

Other (OTH) AF: 0.00275 AC: 166 AN: 60366

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152220 Hom.: 2 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74442

African (AFR) AF: 0.000650 AC: 27 AN: 41548

American (AMR) AF: 0.00694 AC: 106 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00246 AC: 167 AN: 68018

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.00230 Hom.: 2

Bravo AF: 0.00273

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DTNA: BS1, BS2

not specified Benign:3

May 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.His403Tyr in exon 12C of DTNA: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (137/66688) of European chrom osomes and 0.1% (12/11538) of Latino chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org/; dbSNP rs139872140).

May 29, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DTNA c.1216C>T (p.His406Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 277106 control chromosomes (gnomAD). The observed variant frequency is approximately 57-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in DTNA causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1216C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.

Mar 01, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Uncertain:1 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 24, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DTNA c.1216C>T; p.His406Tyr variant (rs139872140), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 46431). This variant is found in the non-Finnish European population with an overall allele frequency of 0.23% (297/129112 alleles) in the Genome Aggregation Database. While this population frequency may be inconsistent with disease, the prevalence of left ventricular non-compaction in the general population is disputed and may be higher than expected (Ross 2020). The histidine at codon 406 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.His406Tyr variant is uncertain at this time. References: Ross SB et al. A systematic review and meta-analysis of the prevalence of left ventricular non-compaction in adults. Eur Heart J. 2020;41(14):1428-1436.

DTNA-related disorder Benign:1

Nov 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.87
MVP		0.68
ClinPred		0.057	T
GERP RS		6.0
Varity_R		0.43
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs139872140; hg19: chr18-32418752; COSMIC: COSV106088722;