rs4820

Positions:

• chr11-18402940-A-G
• chr11-18402940-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000422447.8(LDHA):​c.519A>G​(p.Leu173=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,606,900 control chromosomes in the GnomAD database, including 407,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33255 hom., cov: 32)
  • Exomes 𝑓: 0.72 (374708 hom.)
• Consequence: LDHA ENST00000422447.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0940

Genes affected

LDHA (HGNC:6535): (lactate dehydrogenase A) This gene encodes the A subunit of lactate dehydrogenase enzyme which catalyzes the reversible conversion of pyruvate to lactate with the concomitant oxidation of NADH to NAD in anaerobic glycolysis. The protein is found predominantly in skeletal muscle and belongs to the lactate dehydrogenase family. Mutations in this gene have been linked to exertional myoglobinuria. The human genome contains several non-transcribed pseudogenes of this gene. [provided by RefSeq, Sep 2023]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-18402940-A-G is Benign according to our data. Variant chr11-18402940-A-G is described in ClinVar as [Benign]. Clinvar id is 303915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-18402940-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.094 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDHA	NM_005566.4	c.519A>G	p.Leu173=	synonymous_variant	5/8	ENST00000422447.8	NP_005557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDHA	ENST00000422447.8	c.519A>G	p.Leu173=	synonymous_variant	5/8	1	NM_005566.4	ENSP00000395337	P1

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98959 AN: 151962 Hom.: 33244 Cov.: 32

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.666

GnomAD3 exomes AF: 0.704 AC: 176909 AN: 251186 Hom.: 63058 AF XY: 0.710 AC XY: 96500 AN XY: 135836

Gnomad AFR exome AF: 0.467

Gnomad AMR exome AF: 0.728

Gnomad ASJ exome AF: 0.606

Gnomad EAS exome AF: 0.646

Gnomad SAS exome AF: 0.749

Gnomad FIN exome AF: 0.798

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.713

GnomAD4 exome AF: 0.715 AC: 1040534 AN: 1454820 Hom.: 374708 Cov.: 36 AF XY: 0.717 AC XY: 518833 AN XY: 724062

Gnomad4 AFR exome AF: 0.469

Gnomad4 AMR exome AF: 0.727

Gnomad4 ASJ exome AF: 0.608

Gnomad4 EAS exome AF: 0.660

Gnomad4 SAS exome AF: 0.748

Gnomad4 FIN exome AF: 0.787

Gnomad4 NFE exome AF: 0.721

Gnomad4 OTH exome AF: 0.700

GnomAD4 genome AF: 0.651 AC: 98993 AN: 152080 Hom.: 33255 Cov.: 32 AF XY: 0.657 AC XY: 48869 AN XY: 74344

Gnomad4 AFR AF: 0.473

Gnomad4 AMR AF: 0.701

Gnomad4 ASJ AF: 0.610

Gnomad4 EAS AF: 0.654

Gnomad4 SAS AF: 0.758

Gnomad4 FIN AF: 0.803

Gnomad4 NFE AF: 0.717

Gnomad4 OTH AF: 0.662

Alfa AF: 0.679 Hom.: 15202

Bravo AF: 0.634

EpiCase AF: 0.723

EpiControl AF: 0.725

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.3
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4820; hg19: chr11-18424487;