rs8721

Variant names:

• chr7-107919277-A-T
• rs8721
• NM_000108.5:c.*18A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-107919277-A-T
• chr7-107919277-A-G

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.*18A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,576,250 control chromosomes in the GnomAD database, including 118,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8935 hom., cov: 31)
  • Exomes 𝑓: 0.39 (109762 hom.)
• Consequence: DLD NM_000108.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.54
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-107919277-A-T is Benign according to our data. Variant chr7-107919277-A-T is described in ClinVar as Benign. ClinVar VariationId is 137102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.41 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.*18A>T		3_prime_UTR	Exon 14 of 14	NP_000099.2	A0A024R713
	DLD	NM_001289751.1		c.*18A>T		3_prime_UTR	Exon 13 of 13	NP_001276680.1	P09622
	DLD	NM_001289752.1		c.*18A>T		3_prime_UTR	Exon 13 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.*18A>T		3_prime_UTR	Exon 14 of 14	ENSP00000205402.3	P09622-1
	DLD	ENST00000880448.1		c.*18A>T		3_prime_UTR	Exon 14 of 14	ENSP00000550507.1
	DLD	ENST00000880447.1		c.*18A>T		3_prime_UTR	Exon 14 of 14	ENSP00000550506.1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48057 AN: 151740 Hom.: 8931 Cov.: 31

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.319

GnomAD2 exomes AF: 0.361 AC: 86152 AN: 238486 AF XY: 0.362

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.341

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.374

GnomAD4 exome AF: 0.387 AC: 551602 AN: 1424392 Hom.: 109762 Cov.: 27 AF XY: 0.386 AC XY: 273993 AN XY: 709910

African (AFR) AF: 0.103 AC: 3399 AN: 32874

American (AMR) AF: 0.378 AC: 16707 AN: 44226

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10304 AN: 25880

East Asian (EAS) AF: 0.363 AC: 14275 AN: 39368

South Asian (SAS) AF: 0.283 AC: 23784 AN: 83904

European-Finnish (FIN) AF: 0.392 AC: 18787 AN: 47938

Middle Eastern (MID) AF: 0.334 AC: 1557 AN: 4668

European-Non Finnish (NFE) AF: 0.406 AC: 440742 AN: 1086362

Other (OTH) AF: 0.373 AC: 22047 AN: 59172

GnomAD4 genome AF: 0.316 AC: 48054 AN: 151858 Hom.: 8935 Cov.: 31 AF XY: 0.317 AC XY: 23549 AN XY: 74202

African (AFR) AF: 0.116 AC: 4812 AN: 41476

American (AMR) AF: 0.343 AC: 5230 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1375 AN: 3466

East Asian (EAS) AF: 0.343 AC: 1771 AN: 5160

South Asian (SAS) AF: 0.284 AC: 1368 AN: 4814

European-Finnish (FIN) AF: 0.398 AC: 4183 AN: 10498

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.414 AC: 28084 AN: 67900

Other (OTH) AF: 0.316 AC: 667 AN: 2110

Alfa AF: 0.368 Hom.: 1983

Bravo AF: 0.305

Asia WGS AF: 0.313 AC: 1084 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Pyruvate dehydrogenase E3 deficiency (3)
-	-	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	-0.88
CADD	Benign	1.1
DANN	Benign	0.39
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

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: rs8721; hg19: chr7-107559722; COSMIC: COSV52738193; COSMIC: COSV52738193;