rs111033811
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PM2PP5_Very_StrongBP4BP7
The NM_000155.4(GALT):c.1014C>G(p.Gly338=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G338G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000155.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALT | NM_000155.4 | c.1014C>G | p.Gly338= | synonymous_variant | 10/11 | ENST00000378842.8 | |
GALT | NM_001258332.2 | c.687C>G | p.Gly229= | synonymous_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALT | ENST00000378842.8 | c.1014C>G | p.Gly338= | synonymous_variant | 10/11 | 1 | NM_000155.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251480Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727242
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 27, 2023 | Variant summary: GALT c.1014C>G alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to a frameshift with a premature stop codon at nt1027 (p.Tyr339Leufs*5) (example: Boutron_2012). The variant allele was found at a frequency of 1.2e-05 in 251480 control chromosomes (gnomAD). c.1014C>G has been reported in the literature in individuals affected with Galactosemia (examples: Boutron_2012, Lacombe_2015, Yuzyuk_2018 and Jezela-Stanek_2021). The following publications have been ascertained in the context of this evaluation (PMID: 22944367, 34030713, 31194895, 25622686). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 31, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change affects codon 338 of the GALT mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GALT protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs111033811, gnomAD 0.003%). This variant has been observed in individual(s) with galactosemia (PMID: 22944367; Invitae). ClinVar contains an entry for this variant (Variation ID: 25316). Studies have shown that this variant results in activation of a new donor splice site in exon 10 and introduces a new termination codon (PMID: 22944367). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 02, 2022 | PP4, PM2, PM3_strong, PS3, PS4 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 18, 2015 | - - |
Galactosemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 15, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at