rs4564

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000108.5(DLD):c.*207G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 476,566 control chromosomes in the GnomAD database, including 94,588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33592 hom., cov: 32)

Exomes 𝑓: 0.61 ( 60996 hom. )

Consequence

DLD
NM_000108.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.00900

Publications

22 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 7-107919466-G-A is Benign according to our data. Variant chr7-107919466-G-A is described in ClinVar as Benign. ClinVar VariationId is 358575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
DLD	NM_000108.5 link	c.*207G>A	3_prime_UTR_variant	Exon 14 of 14	ENST00000205402.10	NP_000099.2
DLD	NM_001289751.1 link	c.*207G>A	3_prime_UTR_variant	Exon 13 of 13		NP_001276680.1
DLD	NM_001289752.1 link	c.*207G>A	3_prime_UTR_variant	Exon 13 of 13		NP_001276681.1
DLD	NM_001289750.1 link	c.*207G>A	3_prime_UTR_variant	Exon 12 of 12		NP_001276679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLD	ENST00000205402.10 link	c.*207G>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_000108.5	ENSP00000205402.3

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99784

AN:

151880

Hom.:

33539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.789

Gnomad AMI

AF:

0.716

Gnomad AMR

AF:

0.632

Gnomad ASJ

AF:

0.601

Gnomad EAS

AF:

0.851

Gnomad SAS

AF:

0.572

Gnomad FIN

AF:

0.613

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.583

Gnomad OTH

AF:

0.633

GnomAD4 exome

AF:

0.608

AC:

197382

AN:

324568

Hom.:

60996

Cov.:

AF XY:

0.605

AC XY:

105292

AN XY:

174008

show subpopulations

African (AFR)

AF:

0.779

AC:

7651

AN:

9826

American (AMR)

AF:

0.617

AC:

7498

AN:

12160

Ashkenazi Jewish (ASJ)

AF:

0.607

AC:

6122

AN:

10090

East Asian (EAS)

AF:

0.865

AC:

18546

AN:

21438

South Asian (SAS)

AF:

0.550

AC:

16962

AN:

30834

European-Finnish (FIN)

AF:

0.604

AC:

10198

AN:

16892

Middle Eastern (MID)

AF:

0.577

AC:

820

AN:

1422

European-Non Finnish (NFE)

AF:

0.581

AC:

117941

AN:

203084

Other (OTH)

AF:

0.619

AC:

11644

AN:

18822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

3524

7048

10572

14096

17620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

592

1184

1776

2368

2960

<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:

0.657

AC:

99899

AN:

151998

Hom.:

33592

Cov.:

AF XY:

0.660

AC XY:

49059

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.789

AC:

32735

AN:

41482

American (AMR)

AF:

0.632

AC:

9644

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.601

AC:

2084

AN:

3468

East Asian (EAS)

AF:

0.850

AC:

4402

AN:

5176

South Asian (SAS)

AF:

0.572

AC:

2758

AN:

4822

European-Finnish (FIN)

AF:

0.613

AC:

6455

AN:

10534

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.583

AC:

39643

AN:

67944

Other (OTH)

AF:

0.635

AC:

1340

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1714

3428

5143

6857

8571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<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:

0.604

Hom.:

14937

Bravo

AF:

0.664

Asia WGS

AF:

0.743

AC:

2581

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leigh syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pyruvate dehydrogenase complex deficiency

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pyruvate dehydrogenase E3 deficiency

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.4

(source)

DANN

Benign

0.49

PhyloP100

-0.0090

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over