rs121964987

Positions:

• chr7-107902340-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000108.5(DLD):​c.214A>G​(p.Lys72Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DLD NM_000108.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.00

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 7-107902340-A-G is Pathogenic according to our data. Variant chr7-107902340-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11964.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLD	NM_000108.5	c.214A>G	p.Lys72Glu	missense_variant	4/14	ENST00000205402.10	NP_000099.2
DLD	NM_001289752.1	c.214A>G	p.Lys72Glu	missense_variant	4/13		NP_001276681.1
DLD	NM_001289751.1	c.198+523A>G		intron_variant			NP_001276680.1
DLD	NM_001289750.1	c.-30-1138A>G		intron_variant			NP_001276679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLD	ENST00000205402.10	c.214A>G	p.Lys72Glu	missense_variant	4/14	1	NM_000108.5	ENSP00000205402.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461508 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pyruvate dehydrogenase E3 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.4	M;.;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D;.;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.028	D;.;D
Polyphen		0.98	D;.;.
Vest4		0.90
MutPred		0.87		Loss of methylation at K72 (P = 0.0185);Loss of methylation at K72 (P = 0.0185);Loss of methylation at K72 (P = 0.0185);
MVP		0.79
MPC		0.69
ClinPred		0.99	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs121964987; hg19: chr7-107542785;