7-107891253-G-A

Position:

• chr7-107891253-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000108.5(DLD):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: DLD NM_000108.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.68

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107891253-G-A is Pathogenic according to our data. Variant chr7-107891253-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2865401.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLD	NM_000108.5	c.3G>A	p.Met1?	start_lost	1/14	ENST00000205402.10
DLD	NM_001289751.1	c.3G>A	p.Met1?	start_lost	1/13
DLD	NM_001289752.1	c.3G>A	p.Met1?	start_lost	1/13
DLD	NM_001289750.1	c.-146G>A		5_prime_UTR_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLD	ENST00000205402.10	c.3G>A	p.Met1?	start_lost	1/14	1	NM_000108.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyruvate dehydrogenase E3 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 18, 2023

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DLD protein in which other variant(s) (p.Ile47Thr) have been determined to be pathogenic (PMID: 16770810). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with DLD-related conditions. This sequence change affects the initiator methionine of the DLD mRNA. The next in-frame methionine is located at codon 100. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.1	N;.;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0080	D;.;D;D
Sift4G	Uncertain	0.020	D;.;D;D
Polyphen		0.063	B;.;B;.
Vest4		0.91
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0065);Gain of catalytic residue at M1 (P = 0.0065);Gain of catalytic residue at M1 (P = 0.0065);Gain of catalytic residue at M1 (P = 0.0065);
MVP		0.52
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-107531698;