rs121964990

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_000108.5(DLD):c.685G>A(p.Gly229Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G229C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

DLD
NM_000108.5 missense, splice_region

Scores

Splicing: ADA: 0.9989

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-107915506-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DLD	NM_000108.5 linkuse as main transcript	c.685G>A	p.Gly229Ser	missense_variant, splice_region_variant	9/14	ENST00000205402.10
DLD	NM_001289751.1 linkuse as main transcript	c.616G>A	p.Gly206Ser	missense_variant, splice_region_variant	8/13
DLD	NM_001289752.1 linkuse as main transcript	c.541G>A	p.Gly181Ser	missense_variant, splice_region_variant	8/13
DLD	NM_001289750.1 linkuse as main transcript	c.388G>A	p.Gly130Ser	missense_variant, splice_region_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLD	ENST00000205402.10 linkuse as main transcript	c.685G>A	p.Gly229Ser	missense_variant, splice_region_variant	9/14	1	NM_000108.5	P1	P09622-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.6

D;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.030

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.91

MutPred

0.73

Gain of catalytic residue at G229 (P = 0.0222);.;.;

MVP

0.69

MPC

0.77

ClinPred

0.99

GERP RS

5.8

Varity_R

0.90

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over