11-18396874-A-G

Variant names:

• chr11-18396874-A-G
• NM_005566.4:c.32A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005566.4(LDHA):​c.32A>G​(p.Asn11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDHA NM_005566.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2666773).

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.32A>G	p.Asn11Ser	missense	Exon 2 of 8	NP_005557.1	P00338-1
	LDHA	NM_001165414.2		c.119A>G	p.Asn40Ser	missense	Exon 2 of 8	NP_001158886.1	P00338-3
	LDHA	NM_001135239.2		c.32A>G	p.Asn11Ser	missense	Exon 2 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.32A>G	p.Asn11Ser	missense	Exon 2 of 8	ENSP00000395337.3	P00338-1
	LDHA	ENST00000542179.1	TSL:1	c.32A>G	p.Asn11Ser	missense	Exon 1 of 7	ENSP00000445331.1	P00338-1
	LDHA	ENST00000545215.5	TSL:1	n.32A>G		non_coding_transcript_exon	Exon 2 of 7	ENSP00000442637.1	F5GWW2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.10
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.019	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Benign	0.17	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.37
MutPred		0.26		Gain of disorder (P = 0.0897)
MVP		0.96
MPC		0.37
ClinPred		0.39	T
GERP RS		5.0
PromoterAI		-0.024	Neutral
Varity_R		0.36
gMVP		0.15
Mutation Taster		=79/21	polymorphism

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

hg19: chr11-18418421;