rs61737438

Variant names:

• chr18-34820913-C-T
• rs61737438
• NM_001386795.1:c.999C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-34820913-C-T
• chr18-34820913-C-A
• chr18-34820913-C-G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001386795.1(DTNA):​c.999C>T​(p.Ile333Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,613,762 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: DTNA NM_001386795.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.1226
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.577
• Publications: 0 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 18-34820913-C-T is Benign according to our data. Variant chr18-34820913-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.577 with no splicing effect.
• BS2: High AC in GnomAd4 at 365 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.999C>T	p.Ile333Ile	splice_region synonymous	Exon 9 of 23	NP_001373724.1	A0A7P0TBH9
	DTNA	NM_001386788.1		c.999C>T	p.Ile333Ile	splice_region synonymous	Exon 9 of 23	NP_001373717.1	Q9Y4J8-17
	DTNA	NM_001390.5		c.999C>T	p.Ile333Ile	splice_region synonymous	Exon 8 of 22	NP_001381.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNA	ENST00000444659.6	TSL:5 MANE Select	c.999C>T	p.Ile333Ile	splice_region synonymous	Exon 9 of 23	ENSP00000405819.2	Q9Y4J8-17
	DTNA	ENST00000598334.5	TSL:1	c.999C>T	p.Ile333Ile	splice_region synonymous	Exon 10 of 20	ENSP00000470152.1	Q9Y4J8-15
	DTNA	ENST00000399121.9	TSL:1	c.999C>T	p.Ile333Ile	splice_region synonymous	Exon 10 of 22	ENSP00000382072.5	Q9Y4J8-14

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 362 AN: 151830 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00803

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000656 AC: 165 AN: 251434 AF XY: 0.000522

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000293 AC: 428 AN: 1461816 Hom.: 3 Cov.: 31 AF XY: 0.000235 AC XY: 171 AN XY: 727212

African (AFR) AF: 0.0100 AC: 336 AN: 33478

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111948

Other (OTH) AF: 0.000861 AC: 52 AN: 60394

GnomAD4 genome AF: 0.00240 AC: 365 AN: 151946 Hom.: 1 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74278

African (AFR) AF: 0.00808 AC: 334 AN: 41346

American (AMR) AF: 0.00157 AC: 24 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67986

Other (OTH) AF: 0.00238 AC: 5 AN: 2102

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.00298

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Left ventricular noncompaction 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	7.9
DANN	Benign	0.86
PhyloP100		-0.58
PromoterAI		-0.10	Neutral
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.010		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: rs61737438; hg19: chr18-32400877;