rs377095724
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_024105.4(ALG12):c.1048G>A(p.Gly350Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,950 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G350G) has been classified as Likely benign.
Frequency
Consequence
NM_024105.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALG12 | NM_024105.4 | c.1048G>A | p.Gly350Arg | missense_variant | 8/10 | ENST00000330817.11 | |
ALG12 | XM_017028936.2 | c.1048G>A | p.Gly350Arg | missense_variant | 8/10 | ||
ALG12 | XM_017028937.2 | c.1048G>A | p.Gly350Arg | missense_variant | 8/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALG12 | ENST00000330817.11 | c.1048G>A | p.Gly350Arg | missense_variant | 8/10 | 1 | NM_024105.4 | P1 | |
ENST00000610245.1 | n.2224C>T | non_coding_transcript_exon_variant | 1/1 | ||||||
ALG12 | ENST00000486602.1 | c.256G>A | p.Gly86Arg | missense_variant | 2/4 | 3 | |||
ALG12 | ENST00000492791.1 | c.524-67G>A | intron_variant, NMD_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152062Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251394Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135918
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727246
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152062Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74280
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 30, 2020 | Variant summary: ALG12 c.1048G>A (p.Gly350Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251394 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1048G>A in individuals affected with ALG12-Congenital Disorder Of Glycosylation and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
ALG12-congenital disorder of glycosylation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2021 | This sequence change replaces glycine with arginine at codon 350 of the ALG12 protein (p.Gly350Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs377095724, ExAC 0.005%). This variant has not been reported in the literature in individuals affected with ALG12-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at