7-107891263-A-G

Variant names:

• chr7-107891263-A-G
• rs767940697
• NM_000108.5:c.13A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000108.5(DLD):​c.13A>G​(p.Ser5Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: DLD NM_000108.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.37
• Publications: 1 publications found

Genes affected

DLD (HGNC:2898): (dihydrolipoamide dehydrogenase) This gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In homodimeric form, the encoded protein functions as a dehydrogenase and is found in several multi-enzyme complexes that regulate energy metabolism. However, as a monomer, this protein can function as a protease. Mutations in this gene have been identified in patients with E3-deficient maple syrup urine disease and lipoamide dehydrogenase deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

DLD Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pyruvate dehydrogenase E3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, G2P, Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1684159).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000108.5. 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
	DLD	NM_000108.5	MANE Select	c.13A>G	p.Ser5Gly	missense	Exon 1 of 14	NP_000099.2	A0A024R713
	DLD	NM_001289751.1		c.13A>G	p.Ser5Gly	missense	Exon 1 of 13	NP_001276680.1	P09622
	DLD	NM_001289752.1		c.13A>G	p.Ser5Gly	missense	Exon 1 of 13	NP_001276681.1	P09622-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLD	ENST00000205402.10	TSL:1 MANE Select	c.13A>G	p.Ser5Gly	missense	Exon 1 of 14	ENSP00000205402.3	P09622-1
	DLD	ENST00000451081.5	TSL:1	n.13A>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000388077.1	F2Z2E3
	DLD	ENST00000880448.1		c.13A>G	p.Ser5Gly	missense	Exon 1 of 14	ENSP00000550507.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152258 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251244 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 727192

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111938

Other (OTH) AF: 0.0000331 AC: 2 AN: 60384

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152258 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pyruvate dehydrogenase E3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.22
Sift	Benign	0.11	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.51
MutPred		0.29		Gain of loop (P = 0.0851)
MVP		0.51
MPC		0.18
ClinPred		0.21	T
GERP RS		5.5
PromoterAI		-0.098	Neutral
Varity_R		0.25
gMVP		0.52
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs767940697; hg19: chr7-107531708;