Genetic Variant NM_001933.5:c.10C>G (chr14-74881963-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001933.5(DLST):c.10C>G(p.Arg4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 1,566,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

DLST
NM_001933.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.06

Publications

0 publications found

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 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

DLST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17404601).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLST	NM_001933.5	MANE Select	c.10C>G	p.Arg4Gly	missense	Exon 1 of 15	NP_001924.2
DLST	NM_001244883.2		c.10C>G	p.Arg4Gly	missense	Exon 1 of 7	NP_001231812.1	B7Z6J1
DLST	NR_033814.2		n.48C>G		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLST	ENST00000334220.9	TSL:1 MANE Select	c.10C>G	p.Arg4Gly	missense	Exon 1 of 15	ENSP00000335304.4	P36957-1
DLST	ENST00000554806.5	TSL:1	c.8C>G	p.Pro3Arg	missense	Exon 1 of 10	ENSP00000451957.1	Q86SW4
DLST	ENST00000555089.5	TSL:1	n.10C>G		non_coding_transcript_exon	Exon 1 of 12	ENSP00000452422.1	G3V5M3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000419

AC:

AN:

191090

AF XY:

0.0000190

show subpopulations

Gnomad AFR exome

AF:

0.000474

Gnomad AMR exome

AF:

0.0000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000290

AC:

AN:

1414344

Hom.:

Cov.:

AF XY:

0.0000256

AC XY:

AN XY:

702394

show subpopulations

African (AFR)

AF:

0.000381

AC:

AN:

31474

American (AMR)

AF:

0.0000240

AC:

AN:

41608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25388

East Asian (EAS)

AF:

0.00

AC:

AN:

36162

South Asian (SAS)

AF:

0.0000244

AC:

AN:

81978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37446

Middle Eastern (MID)

AF:

0.000366

AC:

AN:

5466

European-Non Finnish (NFE)

AF:

0.0000210

AC:

AN:

1096040

Other (OTH)

AF:

0.0000170

AC:

AN:

58782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.000386

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000793

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0068

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.073

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.22

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

PhyloP100

3.1

PROVEAN

Benign

0.55

REVEL

Benign

0.065

Sift

Pathogenic

0.0

MutPred

0.41

Gain of sheet (P = 0.0125)

MVP

0.19

ClinPred

0.19

GERP RS

4.5

PromoterAI

0.014

Neutral

(source)

Varity_R

0.26

Mutation Taster

=275/25

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over