18-34875333-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001386795.1(DTNA):c.1838C>T(p.Pro613Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,614,086 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: DTNA NM_001386795.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 6.17

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 18-34875333-C-T is Benign according to our data. Variant chr18-34875333-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191654.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTNA	NM_001386795.1	c.1838C>T	p.Pro613Leu	missense_variant	18/23	ENST00000444659.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTNA	ENST00000444659.6	c.1838C>T	p.Pro613Leu	missense_variant	18/23	5	NM_001386795.1	P3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251306 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 148 AN: 1461874 Hom.: 1 Cov.: 31 AF XY: 0.000118 AC XY: 86 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	DTNA: PP3 -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DTNA p.Pro586Leu variant was identified in 1 of 310 proband chromosomes (frequency: 0.0032) from European individuals or families with SIDS (Neubauer_2017_PMID:28074886). The variant was identified in a 4 year-old female and was classified as a VUS by the study. The variant was also identified in dbSNP (ID: rs145425478), ClinVar (alias c.1586C>T classified as a VUS by Biesecker Lab/Human Development Section and National Institutes of Health), and LOVD 3.0 databases. The variant was not identified in Cosmic, however it was found in control databases in 34 of 246090 chromosomes at a frequency of 0.000138 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 4 of 22298 chromosomes (freq: 0.000179), European (Non-Finnish) in 26 of 111586 chromosomes (freq: 0.000233), Latino in 3 of 33574 chromosomes (freq: 0.000089), South Asian in 1 of 30780 chromosomes (freq: 0.000032), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, and Other populations. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) do not predict a difference in splicing. The p.Pro586 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the P variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Left ventricular noncompaction 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 586 of the DTNA protein (p.Pro586Leu). This variant is present in population databases (rs145425478, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31568572). ClinVar contains an entry for this variant (Variation ID: 191654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 07, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 06, 2021

Variant summary: DTNA c.1757C>T (p.Pro586Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251306 control chromosomes, predominantly at a frequency of 0.00026 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in DTNA causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1757C>T has been reported in the literature without strong evidence for pathogenicity (example: Campuzano_2018, Kuhnisch_2019). These reports therefore, do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=1) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	0.0060	T
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;.;D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.8	D;.;.;.;.;D;D;.;D;.;D;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;.;.;.;.;D;D;.;D;.;D;.
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;D;D;D;.;.;D;.;.
Vest4		0.46
MVP		0.59
MPC		1.1
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.50
gMVP		0.48

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs145425478; hg19: chr18-32455297;