rs9944927

Positions:

• chr18-34890327-G-A
• chr18-34890327-G-C
• chr18-34890327-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000598334.5(DTNA):​c.2062G>A​(p.Glu688Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,535,714 control chromosomes in the GnomAD database, including 43,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8928 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34516 hom.)
• Consequence: DTNA ENST00000598334.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4859438E-4).
• BP6: Variant 18-34890327-G-A is Benign according to our data. Variant chr18-34890327-G-A is described in ClinVar as [Benign]. Clinvar id is 137181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-34890327-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTNA	NM_001386795.1	c.*2593G>A		3_prime_UTR_variant	23/23	ENST00000444659.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTNA	ENST00000444659.6	c.*2593G>A		3_prime_UTR_variant	23/23	5	NM_001386795.1	P3

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45116 AN: 151828 Hom.: 8893 Cov.: 32

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.275

GnomAD3 exomes AF: 0.202 AC: 27673 AN: 136942 Hom.: 3634 AF XY: 0.202 AC XY: 15041 AN XY: 74366

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.278

Gnomad EAS exome AF: 0.0181

Gnomad SAS exome AF: 0.216

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.222

GnomAD4 exome AF: 0.212 AC: 293115 AN: 1383768 Hom.: 34516 Cov.: 33 AF XY: 0.211 AC XY: 144206 AN XY: 682832

Gnomad4 AFR exome AF: 0.575

Gnomad4 AMR exome AF: 0.143

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.0163

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.208

Gnomad4 OTH exome AF: 0.229

GnomAD4 genome AF: 0.298 AC: 45218 AN: 151946 Hom.: 8928 Cov.: 32 AF XY: 0.292 AC XY: 21708 AN XY: 74274

Gnomad4 AFR AF: 0.563

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.0160

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.275

Alfa AF: 0.222 Hom.: 8290

Bravo AF: 0.312

TwinsUK AF: 0.207 AC: 768

ALSPAC AF: 0.208 AC: 802

ExAC AF: 0.213 AC: 3406

Asia WGS AF: 0.160 AC: 556 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2013	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. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.93
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.00015	T
MutationTaster	Benign	2.2e-11	P;P;P;P;P
Sift4G	Uncertain	0.042	D
Vest4		0.088
MPC		0.36
GERP RS		4.7
gMVP		0.36

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9944927; hg19: chr18-32470291; COSMIC: COSV51991943; COSMIC: COSV51991943;