Genetic Variant DLST:p.Val49Ile (chr14-74885633-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001933.5(DLST):c.145G>A(p.Val49Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,612,968 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 5 hom. )

Consequence

DLST
NM_001933.5 missense, splice_region

Scores

Splicing: ADA: 0.005526

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.47

Variant links:

Genes affected

DLST (HGNC:2911): (dihydrolipoamide S-succinyltransferase) This gene encodes a mitochondrial protein that belongs to the 2-oxoacid dehydrogenase family. This protein is one of the three components (the E2 component) of the 2-oxoglutarate dehydrogenase complex that catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Oct 2011]

DLST links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004732251).

BP6

Variant 14-74885633-G-A is Benign according to our data. Variant chr14-74885633-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2741849.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLST	NM_001933.5 link	c.145G>A	p.Val49Ile	missense_variant, splice_region_variant	Exon 3 of 15	ENST00000334220.9	NP_001924.2	P36957-1A0A024R6C9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLST	ENST00000334220.9 link	c.145G>A	p.Val49Ile	missense_variant, splice_region_variant	Exon 3 of 15	1	NM_001933.5	ENSP00000335304.4		P36957-1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000745

AC:

186

AN:

249692

Hom.:

AF XY:

0.000963

AC XY:

130

AN XY:

134990

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00326

Gnomad FIN exome

AF:

0.0000931

Gnomad NFE exome

AF:

0.000584

Gnomad OTH exome

AF:

0.000986

GnomAD4 exome

AF:

0.000639

AC:

933

AN:

1460682

Hom.:

Cov.:

AF XY:

0.000773

AC XY:

562

AN XY:

726662

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00367

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000491

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000473

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000689

Hom.:

Bravo

AF:

0.000423

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000840

AC:

102

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000982

EpiControl

AF:

0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DLST-related disorder

Benign:1

Apr 25, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.15

Eigen

Benign

-0.14

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.70

M_CAP

Benign

0.0056

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.28

REVEL

Benign

0.026

Sift

Benign

0.28

Sift4G

Benign

0.44

Polyphen

0.0010

Vest4

0.23

MVP

0.26

MPC

0.17

ClinPred

0.019

GERP RS

5.1

Varity_R

0.026

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0055

dbscSNV1_RF

Benign

0.14

SpliceAI score (max)

0.040

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over