7-107919057-A-C

Variant names:

• chr7-107919057-A-C
• rs34453495
• NM_000108.5:c.1422A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000108.5(DLD):​c.1422A>C​(p.Gly474Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,613,950 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G474G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0089 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (113 hom.)
• Consequence: DLD NM_000108.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.780
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 7-107919057-A-C is Benign according to our data. Variant chr7-107919057-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0089 (1356/152324) while in subpopulation NFE AF = 0.0133 (906/68032). AF 95% confidence interval is 0.0126. There are 6 homozygotes in GnomAd4. There are 658 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.1422A>C	p.Gly474Gly	synonymous	Exon 13 of 14	NP_000099.2	A0A024R713
	DLD	NM_001289751.1		c.1353A>C	p.Gly451Gly	synonymous	Exon 12 of 13	NP_001276680.1	P09622
	DLD	NM_001289752.1		c.1278A>C	p.Gly426Gly	synonymous	Exon 12 of 13	NP_001276681.1	P09622-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLD	ENST00000205402.10	TSL:1 MANE Select	c.1422A>C	p.Gly474Gly	synonymous	Exon 13 of 14	ENSP00000205402.3	P09622-1
	DLD	ENST00000880448.1		c.1404A>C	p.Gly468Gly	synonymous	Exon 13 of 14	ENSP00000550507.1
	DLD	ENST00000880447.1		c.1398A>C	p.Gly466Gly	synonymous	Exon 13 of 14	ENSP00000550506.1

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1357 AN: 152206 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00874 AC: 2196 AN: 251288 AF XY: 0.00875

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00602

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0115 AC: 16819 AN: 1461626 Hom.: 113 Cov.: 31 AF XY: 0.0111 AC XY: 8105 AN XY: 727124

African (AFR) AF: 0.00176 AC: 59 AN: 33466

American (AMR) AF: 0.00599 AC: 268 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00570 AC: 149 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86254

European-Finnish (FIN) AF: 0.0182 AC: 972 AN: 53414

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0133 AC: 14786 AN: 1111826

Other (OTH) AF: 0.00898 AC: 542 AN: 60384

GnomAD4 genome AF: 0.00890 AC: 1356 AN: 152324 Hom.: 6 Cov.: 32 AF XY: 0.00883 AC XY: 658 AN XY: 74490

African (AFR) AF: 0.00243 AC: 101 AN: 41558

American (AMR) AF: 0.00582 AC: 89 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0133 AC: 906 AN: 68032

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0117 Hom.: 14

Bravo AF: 0.00787

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Pyruvate dehydrogenase E3 deficiency (4)
-	-	3	not provided (3)
-	-	1	Leigh syndrome (1)
-	-	1	not specified (1)
-	-	1	Pyruvate dehydrogenase complex deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.6
DANN	Benign	0.81
PhyloP100		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34453495; hg19: chr7-107559502;