rs41274310

Variant names:

• chr18-34838086-T-C
• rs41274310
• NM_001386795.1:c.1176-8T>C

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.007986
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.48
• Publications: 2 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):

• left ventricular noncompaction 1

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 46430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 347 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNA	NM_001386795.1	MANE Select	c.1176-8T>C		splice_region intron	N/A	NP_001373724.1	A0A7P0TBH9
	DTNA	NM_001386788.1		c.1176-8T>C		splice_region intron	N/A	NP_001373717.1	Q9Y4J8-17
	DTNA	NM_001390.5		c.1095-8T>C		splice_region intron	N/A	NP_001381.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNA	ENST00000444659.6	TSL:5 MANE Select	c.1176-8T>C		splice_region intron	N/A	ENSP00000405819.2	Q9Y4J8-17
	DTNA	ENST00000598334.5	TSL:1	c.1086-10210T>C		intron	N/A	ENSP00000470152.1	Q9Y4J8-15
	DTNA	ENST00000399121.9	TSL:1	c.1086-10210T>C		intron	N/A	ENSP00000382072.5	Q9Y4J8-14

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

GnomAD2 exomes AF: 0.00279 AC: 699 AN: 250878 AF XY: 0.00304

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 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

African (AFR) AF: 0.000508 AC: 17 AN: 33462

American (AMR) AF: 0.000582 AC: 26 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 345 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00516 AC: 445 AN: 86228

European-Finnish (FIN) AF: 0.000544 AC: 29 AN: 53354

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5762

European-Non Finnish (NFE) AF: 0.00349 AC: 3877 AN: 1111714

Other (OTH) AF: 0.00502 AC: 303 AN: 60356

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

African (AFR) AF: 0.000577 AC: 24 AN: 41584

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4822

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00347 AC: 236 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00381 Hom.: 0

Bravo AF: 0.00213

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00368

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Benign	0.88
PhyloP100		3.5
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs41274310; hg19: chr18-32418050;