Genetic Variant NM_000108.5:c.543A>T (chr7-107905465-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000108.5(DLD):c.543A>T(p.Ile181Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,613,824 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0045 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 25 hom. )

Consequence

DLD
NM_000108.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 0.149

Publications

4 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 7-107905465-A-T is Benign according to our data. Variant chr7-107905465-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137095.

BP7

Synonymous conserved (PhyloP=0.149 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00448 (682/152278) while in subpopulation AMR AF = 0.00981 (150/15294). AF 95% confidence interval is 0.00853. There are 4 homozygotes in GnomAd4. There are 311 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000108.5. 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.543A>T	p.Ile181Ile	synonymous	Exon 7 of 14	NP_000099.2
DLD	NM_001289751.1		c.474A>T	p.Ile158Ile	synonymous	Exon 6 of 13	NP_001276680.1
DLD	NM_001289750.1		c.246A>T	p.Ile82Ile	synonymous	Exon 5 of 12	NP_001276679.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DLD	ENST00000205402.10	TSL:1 MANE Select	c.543A>T	p.Ile181Ile	synonymous	Exon 7 of 14	ENSP00000205402.3
DLD	ENST00000451081.5	TSL:1	n.*290A>T		non_coding_transcript_exon	Exon 7 of 9	ENSP00000388077.1
DLD	ENST00000451081.5	TSL:1	n.*290A>T		3_prime_UTR	Exon 7 of 9	ENSP00000388077.1

Frequencies

GnomAD3 genomes

AF:

0.00450

AC:

684

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00633

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00356

AC:

896

AN:

251416

AF XY:

0.00356

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00477

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00556

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00502

AC:

7339

AN:

1461546

Hom.:

Cov.:

AF XY:

0.00496

AC XY:

3608

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33470

American (AMR)

AF:

0.00508

AC:

227

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00387

AC:

101

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000487

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00600

AC:

6667

AN:

1111762

Other (OTH)

AF:

0.00457

AC:

276

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

354

709

1063

1418

1772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.00448

AC:

682

AN:

152278

Hom.:

Cov.:

AF XY:

0.00418

AC XY:

311

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41580

American (AMR)

AF:

0.00981

AC:

150

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00633

AC:

430

AN:

67974

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

106

141

176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00495

Hom.:

Bravo

AF:

0.00490

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00562

EpiControl

AF:

0.00693

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Pyruvate dehydrogenase E3 deficiency (5)

not specified (2)

Leigh syndrome (1)

Pyruvate dehydrogenase complex deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.7

(source)

DANN

Benign

0.76

PhyloP100

0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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