rs4564

Positions:

• chr7-107919466-G-A
• chr7-107919466-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000108.5(DLD):​c.*207G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 476,566 control chromosomes in the GnomAD database, including 94,588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.66 (33592 hom., cov: 32)
  • Exomes 𝑓: 0.61 (60996 hom.)
• Consequence: DLD NM_000108.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.00900

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-107919466-G-A is Benign according to our data. Variant chr7-107919466-G-A is described in ClinVar as [Benign]. Clinvar id is 358575.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
DLD	NM_000108.5	c.*207G>A		3_prime_UTR_variant	14/14	ENST00000205402.10
DLD	NM_001289750.1	c.*207G>A		3_prime_UTR_variant	12/12
DLD	NM_001289751.1	c.*207G>A		3_prime_UTR_variant	13/13
DLD	NM_001289752.1	c.*207G>A		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLD	ENST00000205402.10	c.*207G>A		3_prime_UTR_variant	14/14	1	NM_000108.5	P1

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99784 AN: 151880 Hom.: 33539 Cov.: 32

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.572

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.633

GnomAD4 exome AF: 0.608 AC: 197382 AN: 324568 Hom.: 60996 Cov.: 3 AF XY: 0.605 AC XY: 105292 AN XY: 174008

Gnomad4 AFR exome AF: 0.779

Gnomad4 AMR exome AF: 0.617

Gnomad4 ASJ exome AF: 0.607

Gnomad4 EAS exome AF: 0.865

Gnomad4 SAS exome AF: 0.550

Gnomad4 FIN exome AF: 0.604

Gnomad4 NFE exome AF: 0.581

Gnomad4 OTH exome AF: 0.619

GnomAD4 genome AF: 0.657 AC: 99899 AN: 151998 Hom.: 33592 Cov.: 32 AF XY: 0.660 AC XY: 49059 AN XY: 74278

Gnomad4 AFR AF: 0.789

Gnomad4 AMR AF: 0.632

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.850

Gnomad4 SAS AF: 0.572

Gnomad4 FIN AF: 0.613

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.635

Alfa AF: 0.594 Hom.: 8473

Bravo AF: 0.664

Asia WGS AF: 0.743 AC: 2581 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Pyruvate dehydrogenase complex deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pyruvate dehydrogenase E3 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs4564; hg19: chr7-107559911;