11-18402940-A-G

Variant names:

• chr11-18402940-A-G
• rs4820
• NM_005566.4:c.519A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005566.4(LDHA):​c.519A>G​(p.Leu173Leu) 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 NM_005566.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0940
• Publications: 26 publications found

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]

LDHA Gene-Disease associations (from GenCC):

• glycogen storage disease due to lactate dehydrogenase M-subunit deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 303915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005566.4. 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
	LDHA	NM_005566.4	MANE Select	c.519A>G	p.Leu173Leu	synonymous	Exon 5 of 8	NP_005557.1	P00338-1
	LDHA	NM_001165414.2		c.606A>G	p.Leu202Leu	synonymous	Exon 5 of 8	NP_001158886.1	P00338-3
	LDHA	NM_001135239.2		c.345A>G	p.Leu115Leu	synonymous	Exon 4 of 7	NP_001128711.1	P00338-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDHA	ENST00000422447.8	TSL:1 MANE Select	c.519A>G	p.Leu173Leu	synonymous	Exon 5 of 8	ENSP00000395337.3	P00338-1
	LDHA	ENST00000542179.1	TSL:1	c.519A>G	p.Leu173Leu	synonymous	Exon 4 of 7	ENSP00000445331.1	P00338-1
	LDHA	ENST00000545215.5	TSL:1	n.*263A>G		non_coding_transcript_exon	Exon 4 of 7	ENSP00000442637.1	F5GWW2

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

GnomAD2 exomes AF: 0.704 AC: 176909 AN: 251186 AF XY: 0.710

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 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

African (AFR) AF: 0.469 AC: 15624 AN: 33294

American (AMR) AF: 0.727 AC: 32497 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 15868 AN: 26088

East Asian (EAS) AF: 0.660 AC: 26188 AN: 39652

South Asian (SAS) AF: 0.748 AC: 64419 AN: 86130

European-Finnish (FIN) AF: 0.787 AC: 42007 AN: 53400

Middle Eastern (MID) AF: 0.713 AC: 4099 AN: 5750

European-Non Finnish (NFE) AF: 0.721 AC: 797687 AN: 1105634

Other (OTH) AF: 0.700 AC: 42145 AN: 60172

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

African (AFR) AF: 0.473 AC: 19604 AN: 41470

American (AMR) AF: 0.701 AC: 10700 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2115 AN: 3466

East Asian (EAS) AF: 0.654 AC: 3387 AN: 5176

South Asian (SAS) AF: 0.758 AC: 3650 AN: 4816

European-Finnish (FIN) AF: 0.803 AC: 8503 AN: 10584

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.717 AC: 48753 AN: 67986

Other (OTH) AF: 0.662 AC: 1399 AN: 2114

Alfa AF: 0.679 Hom.: 15202

Bravo AF: 0.634

EpiCase AF: 0.723

EpiControl AF: 0.725

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.3
DANN	Benign	0.65
PhyloP100		-0.094
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4820; hg19: chr11-18424487; COSMIC: COSV108089874; COSMIC: COSV108089874;