rs377063331
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_000925.4(PDHB):c.701-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000636 in 1,572,778 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000925.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDHB | NM_000925.4 | c.701-3C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000302746.11 | |||
PDHB | NM_001173468.2 | c.647-3C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
PDHB | NM_001315536.2 | c.647-3C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
PDHB | NR_033384.2 | n.807-3C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDHB | ENST00000302746.11 | c.701-3C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000925.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000519 AC: 79AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000414 AC: 104AN: 251430Hom.: 0 AF XY: 0.000405 AC XY: 55AN XY: 135882
GnomAD4 exome AF: 0.000648 AC: 921AN: 1420476Hom.: 1 Cov.: 25 AF XY: 0.000639 AC XY: 453AN XY: 709432
GnomAD4 genome ? AF: 0.000519 AC: 79AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30AN XY: 74452
ClinVar
Submissions by phenotype
Pyruvate dehydrogenase E1-beta deficiency Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2022 | This sequence change falls in intron 7 of the PDHB gene. It does not directly change the encoded amino acid sequence of the PDHB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs377063331, gnomAD 0.08%), 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 PDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 346406). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | PDHB: BP4 - |
Pyruvate dehydrogenase complex deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 05, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at