9-98807701-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PVS1_SupportingBS2
The NM_024642.5(GALNT12):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000617 in 1,150,776 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 (★★).
Frequency
Consequence
NM_024642.5 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000311 AC: 47AN: 150924Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000240 AC: 24AN: 999744Hom.: 0 Cov.: 30 AF XY: 0.0000167 AC XY: 8AN XY: 478320
GnomAD4 genome AF: 0.000311 AC: 47AN: 151032Hom.: 0 Cov.: 32 AF XY: 0.000244 AC XY: 18AN XY: 73830
ClinVar
Submissions by phenotype
not provided Uncertain:2
The GALNT12 c.3G>A variant disrupts the translation initiation codon of the GALNT12 mRNA and is predicted to interfere with GALNT12 protein synthesis, however further research is needed. This variant has been reported in the published literature in individuals with breast cancer (PMID: 36315513 (2022)) and breast cancer and colorectal cancer (PMID: 19617566 (2009)). Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive (PMID: 19617566 (2009)). The frequency of this variant in the general population, 0.0011 (45/41310 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
This sequence change affects the initiator methionine of the GALNT12 mRNA. The next in-frame methionine is located at codon 65. This variant is present in population databases (rs267606839, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Disruption of the initiator codon has been observed in individual(s) with colon cancer and breast cancer (PMID: 19617566, 36315513). ClinVar contains an entry for this variant (Variation ID: 1270). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GALNT12 function (PMID: 19617566). 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. -
not specified Uncertain:1
The p.M1? variant (also known as c.3G>A), located in coding exon 1 of the GALNT12 gene, results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This alteration was reported in an African American woman with colon and breast cancer, and showed absence of protein expression in functional studies (Guda K et al. Proc. Natl. Acad. Sci. U.S.A., 2009 Aug;106:12921-5). This alteration is expected to modify the initiation codon (ATG) resulting in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -
Colorectal cancer, susceptibility to, 1 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at