7-107893265-C-T

Variant names:

• chr7-107893265-C-T
• rs747810875
• NM_000108.5:c.105C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001289750.1(DLD):​c.-44C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,612,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: DLD NM_001289750.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.706
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, G2P, Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-107893265-C-T is Benign according to our data. Variant chr7-107893265-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 255129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289750.1. 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.105C>T	p.Tyr35Tyr	synonymous	Exon 2 of 14	NP_000099.2	A0A024R713
	DLD	NM_001289750.1		c.-44C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	NP_001276679.1	P09622-2
	DLD	NM_001289751.1		c.105C>T	p.Tyr35Tyr	synonymous	Exon 2 of 13	NP_001276680.1	P09622

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLD	ENST00000205402.10	TSL:1 MANE Select	c.105C>T	p.Tyr35Tyr	synonymous	Exon 2 of 14	ENSP00000205402.3	P09622-1
	DLD	ENST00000451081.5	TSL:1	n.105C>T		non_coding_transcript_exon	Exon 2 of 9	ENSP00000388077.1	F2Z2E3
	DLD	ENST00000880448.1		c.105C>T	p.Tyr35Tyr	synonymous	Exon 2 of 14	ENSP00000550507.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 250428 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1460310 Hom.: 0 Cov.: 30 AF XY: 0.0000757 AC XY: 55 AN XY: 726364

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.0000449 AC: 2 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39646

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85978

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1111140

Other (OTH) AF: 0.0000166 AC: 1 AN: 60334

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74352

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	Pyruvate dehydrogenase E3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.085
DANN	Benign	0.30
PhyloP100		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs747810875; hg19: chr7-107533710; COSMIC: COSV52737393;