chr7-107919746-C-T

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.

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.*487C>T		3_prime_UTR	Exon 14 of 14	NP_000099.2
	DLD	NM_001289751.1		c.*487C>T		3_prime_UTR	Exon 13 of 13	NP_001276680.1
	DLD	NM_001289752.1		c.*487C>T		3_prime_UTR	Exon 13 of 13	NP_001276681.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLD	ENST00000205402.10	TSL:1 MANE Select	c.*487C>T		3_prime_UTR	Exon 14 of 14	ENSP00000205402.3
	DLD	ENST00000880448.1		c.*487C>T		3_prime_UTR	Exon 14 of 14	ENSP00000550507.1
	DLD	ENST00000880447.1		c.*487C>T		3_prime_UTR	Exon 14 of 14	ENSP00000550506.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Leigh syndrome (1)
-	-	1	Pyruvate dehydrogenase complex deficiency (1)
-	-	1	Pyruvate dehydrogenase E3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

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;