Genetic Variant NM_005566.4:c.244+588C>A (chr11-18400136-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005566.4(LDHA):c.244+588C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 176,080 control chromosomes in the GnomAD database, including 1,231 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 0.12 ( 1080 hom., cov: 32)

Exomes 𝑓: 0.098 ( 151 hom. )

Consequence

LDHA
NM_005566.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.196

Publications

13 publications found

Variant links:

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)

LDHA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDHA	NM_005566.4 link	c.244+588C>A		intron_variant	Intron 3 of 7	ENST00000422447.8	NP_005557.1	P00338-1V9HWB9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDHA	ENST00000422447.8 link	c.244+588C>A		intron_variant	Intron 3 of 7	1	NM_005566.4	ENSP00000395337.3		P00338-1

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17723

AN:

152098

Hom.:

1076

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.0552

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.0891

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.121

GnomAD4 exome

AF:

0.0977

AC:

2331

AN:

23864

Hom.:

151

Cov.:

AF XY:

0.0960

AC XY:

1196

AN XY:

12460

show subpopulations

African (AFR)

AF:

0.0691

AC:

AN:

246

American (AMR)

AF:

0.140

AC:

451

AN:

3214

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

AN:

300

East Asian (EAS)

AF:

0.0418

AC:

AN:

1724

South Asian (SAS)

AF:

0.0869

AC:

288

AN:

3314

European-Finnish (FIN)

AF:

0.0809

AC:

AN:

618

Middle Eastern (MID)

AF:

0.0806

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0978

AC:

1297

AN:

13266

Other (OTH)

AF:

0.104

AC:

117

AN:

1120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

190

285

380

475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.117

AC:

17742

AN:

152216

Hom.:

1080

Cov.:

AF XY:

0.115

AC XY:

8573

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.113

AC:

4707

AN:

41528

American (AMR)

AF:

0.153

AC:

2338

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

552

AN:

3470

East Asian (EAS)

AF:

0.0546

AC:

283

AN:

5186

South Asian (SAS)

AF:

0.104

AC:

502

AN:

4826

European-Finnish (FIN)

AF:

0.0891

AC:

945

AN:

10604

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8008

AN:

68000

Other (OTH)

AF:

0.123

AC:

261

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

808

1616

2424

3232

4040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.121

Hom.:

1410

Bravo

AF:

0.120

Asia WGS

AF:

0.117

AC:

404

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.9

(source)

DANN

Benign

0.55

PhyloP100

0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over