rs1060503523

Variant names:

• chr18-34794097-T-C
• rs1060503523
• NM_001386795.1:c.209T>C

Your query was ambiguous. Multiple possible variants found:

• chr18-34794097-T-C
• chr18-34794097-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001386795.1(DTNA):​c.209T>C​(p.Leu70Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L70L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DTNA NM_001386795.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.98

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNA	NM_001386795.1	c.209T>C	p.Leu70Pro	missense_variant	Exon 4 of 23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6	c.209T>C	p.Leu70Pro	missense_variant	Exon 4 of 23	5	NM_001386795.1	ENSP00000405819.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jan 07, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Left ventricular noncompaction 1 Uncertain:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 70 of the DTNA protein (p.Leu70Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DTNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 411862). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DTNA protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	.;.;.;.;T;.;.;.;.;.;.;.;.;.;D;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;.
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Uncertain	2.1	M;M;M;.;.;M;M;M;M;M;M;M;.;M;M;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.7	D;.;D;.;.;.;D;D;.;.;.;D;.;.;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;.;D;.;.;.;D;D;.;.;.;D;.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.93	P;.;D;.;.;.;.;.;.;D;P;P;.;.;P;P
Vest4		0.79
MutPred		0.67		Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);.;Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);
MVP		0.77
MPC		1.3
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.86
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1060503523; hg19: chr18-32374061;