14-74891111-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001933.5(DLST):c.386C>T(p.Pro129Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,082 control chromosomes in the GnomAD database, including 1 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 0.000085 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: DLST NM_001933.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16600204).
• BP6: Variant 14-74891111-C-T is Benign according to our data. Variant chr14-74891111-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2337791.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLST	NM_001933.5	c.386C>T	p.Pro129Leu	missense_variant	7/15	ENST00000334220.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLST	ENST00000334220.9	c.386C>T	p.Pro129Leu	missense_variant	7/15	1	NM_001933.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251492 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727194

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000277 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.386C>T (p.P129L) alteration is located in exon 7 (coding exon 7) of the DLST gene. This alteration results from a C to T substitution at nucleotide position 386, causing the proline (P) at amino acid position 129 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

DLST-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 03, 2022

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	0.20
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.31
Sift	Benign	0.20	T;D
Sift4G	Benign	0.21	T;T
Polyphen		1.0	D;.
Vest4		0.77
MutPred		0.48		Gain of catalytic residue at V134 (P = 8e-04);.;
MVP		0.35
MPC		0.38
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.18
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs769413082; hg19: chr14-75357814;