rs104894323
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_020661.4(AICDA):c.441C>A(p.Cys147Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000628 in 1,592,364 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000073 ( 0 hom., cov: 28)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
AICDA
NM_020661.4 stop_gained
NM_020661.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.59
Genes affected
AICDA (HGNC:13203): (activation induced cytidine deaminase) This gene encodes a RNA-editing deaminase that is a member of the cytidine deaminase family. AICDA is specifically expressed and active in germinal center-like B cells. In the germinal center, AICDA is involved in somatic hypermutation, gene conversion, and class-switch recombination of immunoglobulin genes. An epigenetic role in neoplastic transformation and lymphoma progression has been experimentally ascribed to AICDA using mouse models. Defects in this gene are the cause of autosomal recessive hyper-IgM immunodeficiency syndrome type 2 (HIGM2). [provided by RefSeq, Jul 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.261 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-8604909-G-T is Pathogenic according to our data. Variant chr12-8604909-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 5127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AICDA | NM_020661.4 | c.441C>A | p.Cys147Ter | stop_gained | 4/5 | ENST00000229335.11 | |
AICDA | NM_001330343.2 | c.428-17C>A | splice_polypyrimidine_tract_variant, intron_variant | ||||
AICDA | NM_001410970.1 | c.427+306C>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AICDA | ENST00000229335.11 | c.441C>A | p.Cys147Ter | stop_gained | 4/5 | 1 | NM_020661.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000729 AC: 1AN: 137258Hom.: 0 Cov.: 28
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GnomAD3 exomes AF: 0.00000423 AC: 1AN: 236328Hom.: 0 AF XY: 0.00000776 AC XY: 1AN XY: 128838
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GnomAD4 exome AF: 0.00000619 AC: 9AN: 1455106Hom.: 0 Cov.: 57 AF XY: 0.00000691 AC XY: 5AN XY: 724018
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 | Invitae | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Cys147*) in the AICDA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AICDA are known to be pathogenic (PMID: 11007475). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal recessive hyper-IgM syndrome (PMID: 11007475). ClinVar contains an entry for this variant (Variation ID: 5127). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | AICDA: PVS1, PM2 - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
ClinPred
D
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at