rs121964990

Positions:

• chr7-107915506-G-A
• chr7-107915506-G-C
• chr7-107915506-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000108.5(DLD):​c.685G>A​(p.Gly229Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G229C) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DLD NM_000108.5 missense, splice_region
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107915506-G-T is described in Lovd as [Pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLD	NM_000108.5	c.685G>A	p.Gly229Ser	missense_variant, splice_region_variant	9/14	ENST00000205402.10	NP_000099.2
DLD	NM_001289751.1	c.616G>A	p.Gly206Ser	missense_variant, splice_region_variant	8/13		NP_001276680.1
DLD	NM_001289752.1	c.541G>A	p.Gly181Ser	missense_variant, splice_region_variant	8/13		NP_001276681.1
DLD	NM_001289750.1	c.388G>A	p.Gly130Ser	missense_variant, splice_region_variant	7/12		NP_001276679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLD	ENST00000205402.10	c.685G>A	p.Gly229Ser	missense_variant, splice_region_variant	9/14	1	NM_000108.5	ENSP00000205402	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152028 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152028 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.91
MutPred		0.73		Gain of catalytic residue at G229 (P = 0.0222);.;.;
MVP		0.69
MPC		0.77
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.010		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: rs121964990; hg19: chr7-107555951;