NM_005566.4:c.127-1172A>G

Variant names:

• chr11-18398259-A-G
• rs2896526
• NM_005566.4:c.127-1172A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005566.4(LDHA):​c.127-1172A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 152,110 control chromosomes in the GnomAD database, including 1,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (1723 hom., cov: 33)
• Consequence: LDHA NM_005566.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.692
• Publications: 25 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: PanelApp Australia, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDHA	NM_005566.4	c.127-1172A>G		intron_variant	Intron 2 of 7	ENST00000422447.8	NP_005557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDHA	ENST00000422447.8	c.127-1172A>G		intron_variant	Intron 2 of 7	1	NM_005566.4	ENSP00000395337.3

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22138 AN: 151992 Hom.: 1722 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0663

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.164

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.146 AC: 22140 AN: 152110 Hom.: 1723 Cov.: 33 AF XY: 0.143 AC XY: 10634 AN XY: 74356

African (AFR) AF: 0.118 AC: 4906 AN: 41488

American (AMR) AF: 0.167 AC: 2554 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 520 AN: 3472

East Asian (EAS) AF: 0.0656 AC: 340 AN: 5180

South Asian (SAS) AF: 0.143 AC: 689 AN: 4824

European-Finnish (FIN) AF: 0.115 AC: 1210 AN: 10560

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11410 AN: 68000

Other (OTH) AF: 0.163 AC: 344 AN: 2112

Alfa AF: 0.163 Hom.: 7217

Bravo AF: 0.150

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.34
DANN	Benign	0.89
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2896526; hg19: chr11-18419806;