11-18396850-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_005566.4(LDHA):c.8C>T(p.Thr3Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,612,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

LDHA
NM_005566.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.21

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15666535).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000289 (44/152290) while in subpopulation NFE AF= 0.000529 (36/68018). AF 95% confidence interval is 0.000392. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDHA	NM_005566.4 link	c.8C>T	p.Thr3Ile	missense_variant	Exon 2 of 8	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.8C>T	p.Thr3Ile	missense_variant	Exon 2 of 8	1	NM_005566.4	ENSP00000395337.3		P00338-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000295

AC:

AN:

250568

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135494

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000350

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000511

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000491

AC:

717

AN:

1460308

Hom.:

Cov.:

AF XY:

0.000440

AC XY:

320

AN XY:

726482

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000608

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000289

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000335

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000492

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 09, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency

Uncertain:1

Sep 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3 of the LDHA protein (p.Thr3Ile). This variant is present in population databases (rs200251957, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with LDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1046949). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;.;.;.;T;.;.;.;.;D;D;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.060

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.67

.;T;T;T;T;T;T;T;T;.;T;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.16

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.6

M;.;M;M;.;M;.;.;.;M;M;.

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.6

D;D;D;D;D;D;D;D;D;D;D;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.028

D;D;D;D;D;D;D;D;D;D;D;.

Sift4G

Benign

0.11

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0010

B;.;.;.;.;.;.;.;.;B;B;.

Vest4

0.28

MVP

0.98

MPC

0.50

ClinPred

0.070

GERP RS

3.0

Varity_R

0.44

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over