rs267606740
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_015386.3(COG4):c.2197C>T(p.Arg733Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,613,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R733Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_015386.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COG4 | NM_015386.3 | c.2197C>T | p.Arg733Trp | missense_variant | 18/19 | ENST00000323786.10 | |
COG4 | NM_001195139.2 | c.2122C>T | p.Arg708Trp | missense_variant | 17/18 | ||
COG4 | NM_001365426.1 | c.1771C>T | p.Arg591Trp | missense_variant | 19/20 | ||
COG4 | NR_158212.1 | n.2156C>T | non_coding_transcript_exon_variant | 18/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COG4 | ENST00000323786.10 | c.2197C>T | p.Arg733Trp | missense_variant | 18/19 | 1 | NM_015386.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152042Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251156Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135772
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461156Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 726856
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152042Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74260
ClinVar
Submissions by phenotype
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 29, 2019 | ACMG classification criteria: PS3, PS4, PM2, PM3 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2022 | Observed in trans with a submicroscopic deletion in an individual with congenital disorder of glycosylation type II (Reynders et al., 2009); Published functional studies demonstrate a damaging effect on glycosylation (Richardson et al., 2009; Sumya et al., 2021); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also denoted as R729W due to alternative nomenclature; This variant is associated with the following publications: (PMID: 19494034, 34426522, 32064623, 31589614, 34603392, 32730773, 19651599) - |
COG4-congenital disorder of glycosylation Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2009 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at