rs732765

Variant names:

• chr14-74899026-A-G
• rs732765
• NM_001933.5:c.901+527A>G

Variant summary

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

The NM_001933.5(DLST):​c.901+527A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 151,992 control chromosomes in the GnomAD database, including 9,256 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 (9256 hom., cov: 32)
• Consequence: DLST NM_001933.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.409
• Publications: 15 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.523 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.901+527A>G		intron	N/A	NP_001924.2
	DLST	NR_033814.2		n.881+527A>G		intron	N/A
	DLST	NR_045209.2		n.890+527A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLST	ENST00000334220.9	TSL:1 MANE Select	c.901+527A>G		intron	N/A	ENSP00000335304.4
	DLST	ENST00000555089.5	TSL:1	n.*530+527A>G		intron	N/A	ENSP00000452422.1
	DLST	ENST00000875051.1		c.898+527A>G		intron	N/A	ENSP00000545110.1

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48486 AN: 151874 Hom.: 9234 Cov.: 32

Gnomad AFR AF: 0.529

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.287

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

GnomAD4 genome AF: 0.319 AC: 48560 AN: 151992 Hom.: 9256 Cov.: 32 AF XY: 0.322 AC XY: 23883 AN XY: 74244

African (AFR) AF: 0.529 AC: 21925 AN: 41440

American (AMR) AF: 0.267 AC: 4076 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3470

East Asian (EAS) AF: 0.218 AC: 1125 AN: 5168

South Asian (SAS) AF: 0.379 AC: 1829 AN: 4822

European-Finnish (FIN) AF: 0.286 AC: 3009 AN: 10532

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 15082 AN: 67974

Other (OTH) AF: 0.283 AC: 599 AN: 2114

Alfa AF: 0.256 Hom.: 13652

Bravo AF: 0.324

Asia WGS AF: 0.315 AC: 1096 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.41
PhyloP100		0.41
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: rs732765; hg19: chr14-75365729;