rs731952

Variant names:

• chr14-74899744-C-T
• rs731952
• NM_001933.5:c.902-179C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001933.5(DLST):​c.902-179C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 151,948 control chromosomes in the GnomAD database, including 7,721 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (7721 hom., cov: 31)
• Consequence: DLST NM_001933.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.648
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pheochromocytoma/paraganglioma syndrome 7

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• pyruvate dehydrogenase E1-alpha deficiency

  Inheritance: AR Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001933.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLST	NM_001933.5	MANE Select	c.902-179C>T		intron	N/A	NP_001924.2
	DLST	NR_033814.2		n.882-179C>T		intron	N/A
	DLST	NR_045209.2		n.891-179C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLST	ENST00000334220.9	TSL:1 MANE Select	c.902-179C>T		intron	N/A	ENSP00000335304.4	P36957-1
	DLST	ENST00000555089.5	TSL:1	n.*531-179C>T		intron	N/A	ENSP00000452422.1	G3V5M3
	DLST	ENST00000875051.1		c.899-179C>T		intron	N/A	ENSP00000545110.1

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47867 AN: 151830 Hom.: 7712 Cov.: 31

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.318

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.315 AC: 47891 AN: 151948 Hom.: 7721 Cov.: 31 AF XY: 0.316 AC XY: 23489 AN XY: 74262

African (AFR) AF: 0.330 AC: 13676 AN: 41422

American (AMR) AF: 0.269 AC: 4105 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1386 AN: 3470

East Asian (EAS) AF: 0.231 AC: 1192 AN: 5168

South Asian (SAS) AF: 0.293 AC: 1405 AN: 4794

European-Finnish (FIN) AF: 0.383 AC: 4034 AN: 10542

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21114 AN: 67954

Other (OTH) AF: 0.323 AC: 682 AN: 2114

Alfa AF: 0.308 Hom.: 1587

Bravo AF: 0.307

Asia WGS AF: 0.298 AC: 1034 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.30
DANN	Benign	0.35
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs731952; hg19: chr14-75366447; COSMIC: COSV53167862; COSMIC: COSV53167862;