11-18396968-GGTAA-G
Variant summary
Our verdict is Likely benign. Variant got -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
Consequence
NM_005566.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000572 AC: 87AN: 152076Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000557 AC: 140AN: 251456Hom.: 0 AF XY: 0.000530 AC XY: 72AN XY: 135908
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000935 AC: 1367AN: 1461806Hom.: 0 AF XY: 0.000941 AC XY: 684AN XY: 727206
GnomAD4 genome AF: 0.000572 AC: 87AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.000484 AC XY: 36AN XY: 74404
ClinVar
Submissions by phenotype
Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency Uncertain:2
The c.126+1_126+4delGTAA variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. The variant is reported at a frequency of 0.00170 in the European American population of the Exome Sequencing Project. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for glycogen storage disease type XI. -
This sequence change falls in intron 2 of the LDHA gene. It does not directly change the encoded amino acid sequence of the LDHA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs776715682, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 303910). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at