7-107905354-T-C

Variant names:

• chr7-107905354-T-C
• rs10263341
• NM_000108.5:c.439-7T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000108.5(DLD):​c.439-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 1,608,560 control chromosomes in the GnomAD database, including 292,000 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33893 hom., cov: 32)
  • Exomes 𝑓: 0.59 (258107 hom.)
• Consequence: DLD NM_000108.5 splice_region, intron
• Scores: Splicing: ADA: 0.03083
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.04
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-107905354-T-C is Benign according to our data. Variant chr7-107905354-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

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.439-7T>C		splice_region intron	N/A	NP_000099.2
	DLD	NM_001289751.1		c.370-7T>C		splice_region intron	N/A	NP_001276680.1
	DLD	NM_001289752.1		c.438+296T>C		intron	N/A	NP_001276681.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLD	ENST00000205402.10	TSL:1 MANE Select	c.439-7T>C		splice_region intron	N/A	ENSP00000205402.3
	DLD	ENST00000451081.5	TSL:1	n.*186-7T>C		splice_region intron	N/A	ENSP00000388077.1
	DLD	ENST00000880449.1		c.345T>C	p.Phe115Phe	synonymous	Exon 6 of 13	ENSP00000550508.1

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100161 AN: 151832 Hom.: 33841 Cov.: 32

Gnomad AFR AF: 0.796

Gnomad AMI AF: 0.715

Gnomad AMR AF: 0.633

Gnomad ASJ AF: 0.601

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

GnomAD2 exomes AF: 0.613 AC: 153533 AN: 250342 AF XY: 0.607

Gnomad AFR exome AF: 0.794

Gnomad AMR exome AF: 0.579

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.847

Gnomad FIN exome AF: 0.601

Gnomad NFE exome AF: 0.578

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.591 AC: 860786 AN: 1456610 Hom.: 258107 Cov.: 33 AF XY: 0.590 AC XY: 427492 AN XY: 725002

African (AFR) AF: 0.801 AC: 26734 AN: 33366

American (AMR) AF: 0.590 AC: 26380 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 15774 AN: 26090

East Asian (EAS) AF: 0.865 AC: 34295 AN: 39634

South Asian (SAS) AF: 0.557 AC: 47919 AN: 86104

European-Finnish (FIN) AF: 0.597 AC: 31849 AN: 53314

Middle Eastern (MID) AF: 0.576 AC: 3311 AN: 5752

European-Non Finnish (NFE) AF: 0.576 AC: 637682 AN: 1107436

Other (OTH) AF: 0.612 AC: 36842 AN: 60234

GnomAD4 genome AF: 0.660 AC: 100275 AN: 151950 Hom.: 33893 Cov.: 32 AF XY: 0.663 AC XY: 49255 AN XY: 74258

African (AFR) AF: 0.797 AC: 33024 AN: 41456

American (AMR) AF: 0.633 AC: 9663 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2085 AN: 3468

East Asian (EAS) AF: 0.850 AC: 4400 AN: 5178

South Asian (SAS) AF: 0.577 AC: 2781 AN: 4818

European-Finnish (FIN) AF: 0.613 AC: 6471 AN: 10558

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

European-Non Finnish (NFE) AF: 0.584 AC: 39670 AN: 67886

Other (OTH) AF: 0.637 AC: 1342 AN: 2108

Alfa AF: 0.597 Hom.: 50207

Bravo AF: 0.667

Asia WGS AF: 0.745 AC: 2591 AN: 3478

EpiCase AF: 0.584

EpiControl AF: 0.586

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Pyruvate dehydrogenase E3 deficiency (6)
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Leigh syndrome (1)
-	-	1	Pyruvate dehydrogenase complex deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.1
DANN	Benign	0.67
PhyloP100		1.0
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.031
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.10		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: rs10263341; hg19: chr7-107545799; COSMIC: COSV52740399; COSMIC: COSV52740399;