Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000205402.10(DLD):c.249T>C(p.Val83Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,613,914 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 17 hom., cov: 33)

Exomes 𝑓: 0.00086 ( 22 hom. )

Consequence

DLD
ENST00000205402.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.749

Publications

2 publications found

Variant links:

Genes affected

DLD (HGNC:2898): (dihydrolipoamide dehydrogenase) This gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In homodimeric form, the encoded protein functions as a dehydrogenase and is found in several multi-enzyme complexes that regulate energy metabolism. However, as a monomer, this protein can function as a protease. Mutations in this gene have been identified in patients with E3-deficient maple syrup urine disease and lipoamide dehydrogenase deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

DLD Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
pyruvate dehydrogenase E3 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

DLD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 7-107902375-T-C is Benign according to our data. Variant chr7-107902375-T-C is described in ClinVar as Benign. ClinVar VariationId is 137092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.749 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00913 (1390/152316) while in subpopulation AFR AF = 0.0317 (1319/41560). AF 95% confidence interval is 0.0303. There are 17 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000205402.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DLD	NM_000108.5	MANE Select	c.249T>C	p.Val83Val	synonymous	Exon 4 of 14	NP_000099.2
DLD	NM_001289752.1		c.249T>C	p.Val83Val	synonymous	Exon 4 of 13	NP_001276681.1
DLD	NM_001289751.1		c.198+558T>C		intron	N/A	NP_001276680.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DLD	ENST00000205402.10	TSL:1 MANE Select	c.249T>C	p.Val83Val	synonymous	Exon 4 of 14	ENSP00000205402.3
DLD	ENST00000451081.5	TSL:1	n.249T>C		non_coding_transcript_exon	Exon 4 of 9	ENSP00000388077.1
DLD	ENST00000437604.6	TSL:2	c.249T>C	p.Val83Val	synonymous	Exon 4 of 13	ENSP00000387542.2

Frequencies

GnomAD3 genomes

AF:

0.00911

AC:

1387

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0318

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00231

AC:

581

AN:

251418

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.0312

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000857

AC:

1253

AN:

1461598

Hom.:

Cov.:

AF XY:

0.000704

AC XY:

512

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0310

AC:

1036

AN:

33464

American (AMR)

AF:

0.00154

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39622

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111860

Other (OTH)

AF:

0.00162

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00913

AC:

1390

AN:

152316

Hom.:

Cov.:

AF XY:

0.00834

AC XY:

621

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0317

AC:

1319

AN:

41560

American (AMR)

AF:

0.00327

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68018

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

133

199

266

332

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:

0.00463

Hom.:

Bravo

AF:

0.00985

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyruvate dehydrogenase E3 deficiency (4)

not provided (2)

Leigh syndrome (1)

not specified (1)

Pyruvate dehydrogenase complex deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.6

(source)

DANN

Benign

0.79

PhyloP100

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over