NM_000108.5:c.118+2575A>G

Variant names:

• chr7-107895853-A-G
• rs3801937
• NM_000108.5:c.118+2575A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000108.5(DLD):​c.118+2575A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 152,142 control chromosomes in the GnomAD database, including 34,002 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (34002 hom., cov: 32)
• Consequence: DLD NM_000108.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.582
• Publications: 7 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: Genomics England PanelApp, Orphanet, Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLD	NM_000108.5	c.118+2575A>G		intron_variant	Intron 2 of 13	ENST00000205402.10	NP_000099.2
DLD	NM_001289751.1	c.118+2575A>G		intron_variant	Intron 2 of 12		NP_001276680.1
DLD	NM_001289752.1	c.118+2575A>G		intron_variant	Intron 2 of 12		NP_001276681.1
DLD	NM_001289750.1	c.-31+2575A>G		intron_variant	Intron 2 of 11		NP_001276679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLD	ENST00000205402.10	c.118+2575A>G		intron_variant	Intron 2 of 13	1	NM_000108.5	ENSP00000205402.3

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100358 AN: 152024 Hom.: 33949 Cov.: 32

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.715

Gnomad AMR AF: 0.633

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.635

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.660 AC: 100473 AN: 152142 Hom.: 34002 Cov.: 32 AF XY: 0.664 AC XY: 49358 AN XY: 74370

African (AFR) AF: 0.798 AC: 33105 AN: 41498

American (AMR) AF: 0.633 AC: 9665 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2100 AN: 3470

East Asian (EAS) AF: 0.850 AC: 4409 AN: 5186

South Asian (SAS) AF: 0.577 AC: 2784 AN: 4826

European-Finnish (FIN) AF: 0.613 AC: 6486 AN: 10582

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.585 AC: 39739 AN: 67988

Other (OTH) AF: 0.637 AC: 1346 AN: 2112

Alfa AF: 0.627 Hom.: 4696

Bravo AF: 0.668

Asia WGS AF: 0.746 AC: 2596 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3801937; hg19: chr7-107536298; COSMIC: COSV107223049; COSMIC: COSV107223049;