rs1555778803

Variant names:

• chr18-34766041-T-G
• rs1555778803
• NM_001386795.1:c.148T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001386795.1(DTNA):​c.148T>G​(p.Leu50Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/24 in silico tools predict 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DTNA NM_001386795.1 missense, splice_region
• Scores: Splicing: ADA: 0.0001585
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.161
• 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

DTNA-AS1 (HGNC:58208):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.148T>G	p.Leu50Val	missense splice_region	Exon 3 of 23	NP_001373724.1	A0A7P0TBH9
	DTNA	NM_001386788.1		c.148T>G	p.Leu50Val	missense splice_region	Exon 3 of 23	NP_001373717.1	Q9Y4J8-17
	DTNA	NM_001390.5		c.148T>G	p.Leu50Val	missense splice_region	Exon 2 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.148T>G	p.Leu50Val	missense splice_region	Exon 3 of 23	ENSP00000405819.2	Q9Y4J8-17
	DTNA	ENST00000598334.5	TSL:1	c.148T>G	p.Leu50Val	missense splice_region	Exon 4 of 20	ENSP00000470152.1	Q9Y4J8-15
	DTNA	ENST00000399121.9	TSL:1	c.148T>G	p.Leu50Val	missense splice_region	Exon 4 of 22	ENSP00000382072.5	Q9Y4J8-14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461330 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726964

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111636

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Left ventricular noncompaction 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.16
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.24
Sift	Benign	0.15	T
Sift4G	Benign	0.22	T
Polyphen		0.010	B
Vest4		0.75
MutPred		0.85		Gain of methylation at K47 (P = 0.0673)
MVP		0.66
MPC		0.34
ClinPred		0.20	T
GERP RS		0.17
Varity_R		0.12
gMVP		0.70
Mutation Taster		=264/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.020
SpliceAI score (max)		0.0		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: rs1555778803; hg19: chr18-32346005;