rs104894322
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_020661.4(AICDA):c.415A>G(p.Met139Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M139T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020661.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AICDA | NM_020661.4 | c.415A>G | p.Met139Val | missense_variant | 3/5 | ENST00000229335.11 | NP_065712.1 | |
AICDA | NM_001330343.2 | c.415A>G | p.Met139Val | missense_variant | 3/5 | NP_001317272.1 | ||
AICDA | NM_001410970.1 | c.415A>G | p.Met139Val | missense_variant | 3/4 | NP_001397899.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AICDA | ENST00000229335.11 | c.415A>G | p.Met139Val | missense_variant | 3/5 | 1 | NM_020661.4 | ENSP00000229335.6 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hyper-IgM syndrome type 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 01, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met139 amino acid residue in AICDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27142677). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects AICDA function (PMID: 22715099). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5126). This missense change has been observed in individuals with autosomal recessive hyper IgM syndrome (HIGM) (PMID: 11007475, 16964591). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 139 of the AICDA protein (p.Met139Val). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | AICDA: PM3:Strong, PM2, PM5, PP3, PS3:Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at