rs143759519
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3BP4_ModerateBS1BS2
The NM_002863.5(PYGL):c.1145C>T(p.Pro382Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,614,214 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002863.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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PYGL | ENST00000216392.8 | c.1145C>T | p.Pro382Leu | missense_variant | Exon 10 of 20 | 1 | NM_002863.5 | ENSP00000216392.7 | ||
PYGL | ENST00000532462.5 | c.1145C>T | p.Pro382Leu | missense_variant | Exon 10 of 20 | 1 | ENSP00000431657.1 | |||
PYGL | ENST00000544180.6 | c.1043C>T | p.Pro348Leu | missense_variant | Exon 9 of 19 | 2 | ENSP00000443787.1 | |||
PYGL | ENST00000528757.2 | n.22C>T | non_coding_transcript_exon_variant | Exon 1 of 2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.00426 AC: 649AN: 152242Hom.: 4 Cov.: 33
GnomAD3 exomes AF: 0.00411 AC: 1032AN: 251388Hom.: 6 AF XY: 0.00424 AC XY: 576AN XY: 135882
GnomAD4 exome AF: 0.00559 AC: 8175AN: 1461854Hom.: 31 Cov.: 32 AF XY: 0.00554 AC XY: 4028AN XY: 727224
GnomAD4 genome AF: 0.00426 AC: 649AN: 152360Hom.: 4 Cov.: 33 AF XY: 0.00389 AC XY: 290AN XY: 74506
ClinVar
Submissions by phenotype
Glycogen storage disease, type VI Uncertain:5Benign:3
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
This variant was identified as compound heterozygous. -
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not specified Benign:1
Variant summary: PYGL c.1145C>T (p.Pro382Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 251388 control chromosomes in the gnomAD database, including 6 homozygotes. c.1145C>T has been reported in the literature at a compound heterozygous state along with a second pathogenic missense in an individual affected with Glycogen storage disease (example, Davit-Spraul_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen storage disease, type VI. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 21646031). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Benign/Likely benign, n=3; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign. -
PYGL-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
PYGL: PP3, BS2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at