7-107905354-T-C

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.03083
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.04

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 -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 [Likely_benign]. Clinvar id is 137094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107905354-T-C is described in Lovd as [Benign].
• 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.439-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000205402.10
DLD	NM_001289750.1	c.142-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DLD	NM_001289751.1	c.370-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DLD	NM_001289752.1	c.438+296T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLD	ENST00000205402.10	c.439-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000108.5	P1

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

GnomAD3 exomes AF: 0.613 AC: 153533 AN: 250342 Hom.: 47963 AF XY: 0.607 AC XY: 82190 AN XY: 135480

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 SAS exome AF: 0.560

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

Gnomad4 AFR exome AF: 0.801

Gnomad4 AMR exome AF: 0.590

Gnomad4 ASJ exome AF: 0.605

Gnomad4 EAS exome AF: 0.865

Gnomad4 SAS exome AF: 0.557

Gnomad4 FIN exome AF: 0.597

Gnomad4 NFE exome AF: 0.576

Gnomad4 OTH exome AF: 0.612

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

Gnomad4 AFR AF: 0.797

Gnomad4 AMR AF: 0.633

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.850

Gnomad4 SAS AF: 0.577

Gnomad4 FIN AF: 0.613

Gnomad4 NFE AF: 0.584

Gnomad4 OTH AF: 0.637

Alfa AF: 0.591 Hom.: 39703

Bravo AF: 0.667

Asia WGS AF: 0.745 AC: 2591 AN: 3478

EpiCase AF: 0.584

EpiControl AF: 0.586

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E3 deficiency Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Pyruvate dehydrogenase complex deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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. -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	8.1
Dann	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs10263341; hg19: chr7-107545799; COSMIC: COSV52740399; COSMIC: COSV52740399;