dbSNP rs587688778: DLAT:c.-157G>A (chr11-112025316-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000713569.1(DLAT):c.-157G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,022,826 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0090 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 9 hom. )

Consequence

DLAT
ENST00000713569.1 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.648

Publications

0 publications found

Variant links:

Genes affected

DLAT (HGNC:2896): (dihydrolipoamide S-acetyltransferase) This gene encodes component E2 of the multi-enzyme pyruvate dehydrogenase complex (PDC). PDC resides in the inner mitochondrial membrane and catalyzes the conversion of pyruvate to acetyl coenzyme A. The protein product of this gene, dihydrolipoamide acetyltransferase, accepts acetyl groups formed by the oxidative decarboxylation of pyruvate and transfers them to coenzyme A. Dihydrolipoamide acetyltransferase is the antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with the autoimmune liver disease primary biliary cirrhosis (PBC). In PBC, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. PBC enventually leads to cirrhosis and liver failure. Mutations in this gene are also a cause of pyruvate dehydrogenase E2 deficiency which causes primary lactic acidosis in infancy and early childhood.[provided by RefSeq, Oct 2009]

DLAT Gene-Disease associations (from GenCC):

pyruvate dehydrogenase E2 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

DLAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 11-112025316-G-A is Benign according to our data. Variant chr11-112025316-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1210737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00897 (1367/152344) while in subpopulation AFR AF = 0.0301 (1253/41584). AF 95% confidence interval is 0.0287. There are 10 homozygotes in GnomAd4. There are 648 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000713569.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DLAT	NM_001931.5	MANE Select	c.-157G>A	upstream_gene	N/A	NP_001922.2
DLAT	NM_001372031.1		c.-157G>A	upstream_gene	N/A	NP_001358960.1
DLAT	NM_001372032.1		c.-157G>A	upstream_gene	N/A	NP_001358961.1	A0A7P0TBE2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DLAT	ENST00000713569.1		c.-157G>A	5_prime_UTR	Exon 1 of 14	ENSP00000518862.1	P10515
DLAT	ENST00000280346.11	TSL:1 MANE Select	c.-157G>A	upstream_gene	N/A	ENSP00000280346.7	P10515
DLAT	ENST00000915657.1		c.-157G>A	upstream_gene	N/A	ENSP00000585716.1

Frequencies

GnomAD3 genomes

AF:

0.00895

AC:

1363

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00955

GnomAD4 exome

AF:

0.00111

AC:

970

AN:

870482

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

441

AN XY:

439336

show subpopulations

African (AFR)

AF:

0.0339

AC:

735

AN:

21682

American (AMR)

AF:

0.00210

AC:

AN:

30990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18442

East Asian (EAS)

AF:

0.00

AC:

AN:

33172

South Asian (SAS)

AF:

0.000198

AC:

AN:

60630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32152

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

2944

European-Non Finnish (NFE)

AF:

0.0000730

AC:

AN:

630244

Other (OTH)

AF:

0.00254

AC:

102

AN:

40226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00897

AC:

1367

AN:

152344

Hom.:

Cov.:

AF XY:

0.00870

AC XY:

648

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0301

AC:

1253

AN:

41584

American (AMR)

AF:

0.00522

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68030

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00867

Hom.:

Bravo

AF:

0.0104

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

2.1

(source)

DANN

Benign

0.72

PhyloP100

-0.65

PromoterAI

0.057

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over