rs77320474

chr18-34851834-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001386795.1(DTNA):c.1438C>A(p.Pro480Thr) variant causes a missense change. The variant allele was found at a frequency of 0.001 in 1,613,964 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (8 hom.)
• Consequence: DTNA NM_001386795.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.40

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=0.0038781166).
• BP6: Variant 18-34851834-C-A is Benign according to our data. Variant chr18-34851834-C-A is described in ClinVar as [Benign]. Clinvar id is 46411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-34851834-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00549 (836/152336) while in subpopulation AFR AF= 0.0191 (795/41574). AF 95% confidence interval is 0.018. There are 6 homozygotes in gnomad4. There are 385 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 830 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTNA	NM_001386795.1	c.1438C>A	p.Pro480Thr	missense_variant	15/23	ENST00000444659.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTNA	ENST00000444659.6	c.1438C>A	p.Pro480Thr	missense_variant	15/23	5	NM_001386795.1	P3

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 830 AN: 152218 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00147 AC: 368 AN: 251124 Hom.: 3 AF XY: 0.00105 AC XY: 142 AN XY: 135714

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000534 AC: 781 AN: 1461628 Hom.: 8 Cov.: 31 AF XY: 0.000457 AC XY: 332 AN XY: 727134

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152336 Hom.: 6 Cov.: 32 AF XY: 0.00517 AC XY: 385 AN XY: 74486

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00106 Hom.: 1

Bravo AF: 0.00623

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00191 AC: 232

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2012	Pro396Thr in Exon 14 of DTNA: This variant is not expected to have clinical sign ificance because it has been identified in 1.9% (72/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs77320474). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2014	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. -

Primary dilated cardiomyopathy;C1135191:Systolic heart failure Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 08, 2019

- -

Left ventricular noncompaction 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	0.080
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;.;D;T;D;.;T;D;D;T;D;T;D
MetaRNN	Benign	0.0039	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.0	N;.;.;.;.;.;.;N;.;N;N;.;N;.;.;N;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.075	T;.;.;.;.;.;.;T;.;T;T;.;D;.;.;D;.;.
Sift4G	Benign	0.41	T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;B;B;B;.;B;B;.;.;P;B;.;.;.
Vest4		0.21
MVP		0.48
MPC		0.41
ClinPred		0.0066	T
GERP RS		5.7
Varity_R		0.087
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77320474; hg19: chr18-32431798;