rs4518

Variant names:

• chr7-107919746-C-T
• rs4518
• NM_000108.5:c.*487C>T

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.*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
• Publications: 22 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: Genomics England PanelApp, Orphanet, Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-107919746-C-T is Benign according to our data. Variant chr7-107919746-C-T is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
DLD	NM_000108.5	c.*487C>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000205402.10	NP_000099.2
DLD	NM_001289751.1	c.*487C>T		3_prime_UTR_variant	Exon 13 of 13		NP_001276680.1
DLD	NM_001289752.1	c.*487C>T		3_prime_UTR_variant	Exon 13 of 13		NP_001276681.1
DLD	NM_001289750.1	c.*487C>T		3_prime_UTR_variant	Exon 12 of 12		NP_001276679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLD	ENST00000205402.10	c.*487C>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_000108.5	ENSP00000205402.3

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

African (AFR) AF: 0.833 AC: 10 AN: 12

American (AMR) AF: 0.545 AC: 303 AN: 556

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 12 AN: 22

East Asian (EAS) AF: 0.656 AC: 143 AN: 218

South Asian (SAS) AF: 0.490 AC: 192 AN: 392

European-Finnish (FIN) AF: 0.559 AC: 19 AN: 34

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.571 AC: 1348 AN: 2362

Other (OTH) AF: 0.594 AC: 76 AN: 128

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

African (AFR) AF: 0.791 AC: 32811 AN: 41480

American (AMR) AF: 0.643 AC: 9829 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2113 AN: 3468

East Asian (EAS) AF: 0.851 AC: 4396 AN: 5168

South Asian (SAS) AF: 0.572 AC: 2754 AN: 4816

European-Finnish (FIN) AF: 0.613 AC: 6474 AN: 10556

Middle Eastern (MID) AF: 0.640 AC: 187 AN: 292

European-Non Finnish (NFE) AF: 0.594 AC: 40335 AN: 67918

Other (OTH) AF: 0.644 AC: 1362 AN: 2114

Alfa AF: 0.613 Hom.: 35834

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 complex deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4518; hg19: chr7-107560191;