7-107919746-C-T

Position:

• chr7-107919746-C-T

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.*487C>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 0.662 in 155,728 control chromosomes in the GnomAD database, including 34,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34233 hom., cov: 32)
  • Exomes 𝑓: 0.56 (631 hom.)
• Consequence: DLD NM_000108.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.229

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=-0.88).
• BP6: Variant 7-107919746-C-T is Benign according to our data. Variant chr7-107919746-C-T is described in ClinVar as [Benign]. Clinvar id is 358579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.83 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLD	NM_000108.5	c.*487C>T		3_prime_UTR_variant	14/14	ENST00000205402.10	NP_000099.2
DLD	NM_001289750.1	c.*487C>T		3_prime_UTR_variant	12/12		NP_001276679.1
DLD	NM_001289751.1	c.*487C>T		3_prime_UTR_variant	13/13		NP_001276680.1
DLD	NM_001289752.1	c.*487C>T		3_prime_UTR_variant	13/13		NP_001276681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLD	ENST00000205402.10	c.*487C>T		3_prime_UTR_variant	14/14	1	NM_000108.5	ENSP00000205402	P1
DLD	ENST00000417551.5	c.*124+363C>T		intron_variant, NMD_transcript_variant		5		ENSP00000390667
DLD	ENST00000440410.5			downstream_gene_variant		2		ENSP00000417016

Frequencies

GnomAD3 genomes AF: 0.664 AC: 100799 AN: 151884 Hom.: 34182 Cov.: 32

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.572

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.642

GnomAD4 exome AF: 0.564 AC: 2103 AN: 3726 Hom.: 631 Cov.: 0 AF XY: 0.570 AC XY: 1187 AN XY: 2084

Gnomad4 AFR exome AF: 0.833

Gnomad4 AMR exome AF: 0.545

Gnomad4 ASJ exome AF: 0.545

Gnomad4 EAS exome AF: 0.656

Gnomad4 SAS exome AF: 0.490

Gnomad4 FIN exome AF: 0.559

Gnomad4 NFE exome AF: 0.571

Gnomad4 OTH exome AF: 0.594

GnomAD4 genome AF: 0.664 AC: 100913 AN: 152002 Hom.: 34233 Cov.: 32 AF XY: 0.667 AC XY: 49542 AN XY: 74298

Gnomad4 AFR AF: 0.791

Gnomad4 AMR AF: 0.643

Gnomad4 ASJ AF: 0.609

Gnomad4 EAS AF: 0.851

Gnomad4 SAS AF: 0.572

Gnomad4 FIN AF: 0.613

Gnomad4 NFE AF: 0.594

Gnomad4 OTH AF: 0.644

Alfa AF: 0.606 Hom.: 26427

Bravo AF: 0.672

Asia WGS AF: 0.739 AC: 2570 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

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. -

Pyruvate dehydrogenase E3 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs4518; hg19: chr7-107560191;