11-18396968-GGTAA-G

Variant names:

• chr11-18396968-GGTAA-G
• rs776715682
• NM_005566.4:c.126+3_126+6delAAGT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_005566.4(LDHA):​c.126+3_126+6delAAGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000572 in 152,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDHA NM_005566.4 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.96
• 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000572 (87/152194) while in subpopulation NFE AF = 0.00106 (72/68016). AF 95% confidence interval is 0.000861. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.126+3_126+6delAAGT		splice_region intron	N/A	NP_005557.1	P00338-1
	LDHA	NM_001165414.2		c.213+3_213+6delAAGT		splice_region intron	N/A	NP_001158886.1	P00338-3
	LDHA	NM_001135239.2		c.126+3_126+6delAAGT		splice_region intron	N/A	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.126+3_126+6delAAGT		splice_region intron	N/A	ENSP00000395337.3	P00338-1
	LDHA	ENST00000542179.1	TSL:1	c.126+3_126+6delAAGT		splice_region intron	N/A	ENSP00000445331.1	P00338-1
	LDHA	ENST00000545215.5	TSL:1	n.126+3_126+6delAAGT		splice_region intron	N/A	ENSP00000442637.1	F5GWW2

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152076 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000557 AC: 140 AN: 251456 AF XY: 0.000530

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000935 AC: 1367 AN: 1461806 Hom.: 0 AF XY: 0.000941 AC XY: 684 AN XY: 727206

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00111 AC: 1239 AN: 1111932

Other (OTH) AF: 0.00109 AC: 66 AN: 60394

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000484 AC XY: 36 AN XY: 74404

African (AFR) AF: 0.000193 AC: 8 AN: 41520

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000514

EpiCase AF: 0.000818

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=22/78	disease causing

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: rs776715682; hg19: chr11-18418515;