dbSNP rs61752915: LDHA:p.Pro129Pro (chr11-18400979-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005566.4(LDHA):c.387G>A(p.Pro129Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,860 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 31)

Exomes 𝑓: 0.014 ( 188 hom. )

Consequence

LDHA
NM_005566.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0380

Publications

4 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

LDHA links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005566.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 11-18400979-G-A is Benign according to our data. Variant chr11-18400979-G-A is described in ClinVar as Benign. ClinVar VariationId is 303913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.038 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0104 (1578/151682) while in subpopulation NFE AF = 0.0168 (1143/67948). AF 95% confidence interval is 0.016. There are 14 homozygotes in GnomAd4. There are 749 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDHA	NM_005566.4	MANE Select	c.387G>A	p.Pro129Pro	synonymous	Exon 4 of 8	NP_005557.1	P00338-1
LDHA	NM_001165414.2		c.474G>A	p.Pro158Pro	synonymous	Exon 4 of 8	NP_001158886.1	P00338-3
LDHA	NM_001165415.2		c.387G>A	p.Pro129Pro	synonymous	Exon 4 of 7	NP_001158887.1	P00338-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDHA	ENST00000422447.8	TSL:1 MANE Select	c.387G>A	p.Pro129Pro	synonymous	Exon 4 of 8	ENSP00000395337.3	P00338-1
LDHA	ENST00000542179.1	TSL:1	c.387G>A	p.Pro129Pro	synonymous	Exon 3 of 7	ENSP00000445331.1	P00338-1
LDHA	ENST00000545215.5	TSL:1	n.*131G>A		non_coding_transcript_exon	Exon 3 of 7	ENSP00000442637.1	F5GWW2

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1580

AN:

151570

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00240

Gnomad AMI

AF:

0.0736

Gnomad AMR

AF:

0.00224

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0168

Gnomad OTH

AF:

0.00529

GnomAD2 exomes

AF:

0.00993

AC:

2493

AN:

251152

AF XY:

0.00997

show subpopulations

Gnomad AFR exome

AF:

0.00221

Gnomad AMR exome

AF:

0.00341

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.00995

GnomAD4 exome

AF:

0.0139

AC:

20354

AN:

1461178

Hom.:

188

Cov.:

AF XY:

0.0137

AC XY:

9994

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

33464

American (AMR)

AF:

0.00333

AC:

149

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00337

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.00407

AC:

351

AN:

86236

European-Finnish (FIN)

AF:

0.0149

AC:

795

AN:

53388

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0163

AC:

18107

AN:

1111462

Other (OTH)

AF:

0.0129

AC:

778

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

881

1762

2644

3525

4406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

656

1312

1968

2624

3280

<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:

0.0104

AC:

1578

AN:

151682

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

749

AN XY:

74128

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

41370

American (AMR)

AF:

0.00224

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00353

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0186

AC:

194

AN:

10428

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0168

AC:

1143

AN:

67948

Other (OTH)

AF:

0.00523

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

158

237

316

395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0115

Hom.:

Bravo

AF:

0.00884

EpiCase

AF:

0.0143

EpiControl

AF:

0.0127

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency (3)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

7.3

(source)

DANN

Benign

0.88

PhyloP100

-0.038

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over