rs541157

Variant names:

• chr18-34875415-T-C
• rs541157
• NM_001386795.1:c.1903+17T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001386795.1(DTNA):​c.1903+17T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,613,804 control chromosomes in the GnomAD database, including 13,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2251 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11504 hom.)
• Consequence: DTNA NM_001386795.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-34875415-T-C is Benign according to our data. Variant chr18-34875415-T-C is described in ClinVar as Benign. ClinVar VariationId is 137178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

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.1903+17T>C		intron	N/A	NP_001373724.1
	DTNA	NM_001386788.1		c.1903+17T>C		intron	N/A	NP_001373717.1
	DTNA	NM_001390.5		c.1822+17T>C		intron	N/A	NP_001381.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNA	ENST00000444659.6	TSL:5 MANE Select	c.1903+17T>C		intron	N/A	ENSP00000405819.2
	DTNA	ENST00000598334.5	TSL:1	c.1642+17T>C		intron	N/A	ENSP00000470152.1
	DTNA	ENST00000399121.9	TSL:1	c.1663+17T>C		intron	N/A	ENSP00000382072.5

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24173 AN: 152018 Hom.: 2248 Cov.: 32

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.140

GnomAD2 exomes AF: 0.119 AC: 29765 AN: 250264 AF XY: 0.121

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.0610

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.0139

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.120 AC: 175307 AN: 1461668 Hom.: 11504 Cov.: 32 AF XY: 0.121 AC XY: 87706 AN XY: 727124

African (AFR) AF: 0.271 AC: 9066 AN: 33480

American (AMR) AF: 0.0664 AC: 2971 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3028 AN: 26134

East Asian (EAS) AF: 0.00756 AC: 300 AN: 39698

South Asian (SAS) AF: 0.131 AC: 11277 AN: 86256

European-Finnish (FIN) AF: 0.155 AC: 8237 AN: 53260

Middle Eastern (MID) AF: 0.118 AC: 679 AN: 5768

European-Non Finnish (NFE) AF: 0.119 AC: 132606 AN: 1111956

Other (OTH) AF: 0.118 AC: 7143 AN: 60396

GnomAD4 genome AF: 0.159 AC: 24202 AN: 152136 Hom.: 2251 Cov.: 32 AF XY: 0.160 AC XY: 11889 AN XY: 74396

African (AFR) AF: 0.264 AC: 10931 AN: 41470

American (AMR) AF: 0.104 AC: 1587 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 390 AN: 3470

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5178

South Asian (SAS) AF: 0.124 AC: 599 AN: 4814

European-Finnish (FIN) AF: 0.164 AC: 1741 AN: 10596

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8505 AN: 67988

Other (OTH) AF: 0.138 AC: 293 AN: 2116

Alfa AF: 0.134 Hom.: 1417

Bravo AF: 0.157

Asia WGS AF: 0.0750 AC: 261 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Left ventricular noncompaction 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.52
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs541157; hg19: chr18-32455379;