rs104894324

chr12-8606951-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020661.4(AICDA):c.70C>T(p.Arg24Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,860 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: AICDA NM_020661.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a chain Single-stranded DNA cytosine deaminase (size 197) in uniprot entity AICDA_HUMAN there are 23 pathogenic changes around while only 3 benign (88%) in NM_020661.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-8606950-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 863582.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 12-8606951-G-A is Pathogenic according to our data. Variant chr12-8606951-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5122.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.70C>T	p.Arg24Trp	missense_variant	2/5	ENST00000229335.11
AICDA	NM_001330343.2	c.70C>T	p.Arg24Trp	missense_variant	2/5
AICDA	NM_001410970.1	c.70C>T	p.Arg24Trp	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AICDA	ENST00000229335.11	c.70C>T	p.Arg24Trp	missense_variant	2/5	1	NM_020661.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249542 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461860 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 16, 2023	ClinVar contains an entry for this variant (Variation ID: 5122). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg24 amino acid residue in AICDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27577878; Invitae). 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. This missense change has been observed in individuals with autosomal recessive hyper Ig M syndrome (PMID: 11007475, 26551569). This variant is present in population databases (rs104894324, gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 24 of the AICDA protein (p.Arg24Trp). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with AICDA related disorder (ClinVar ID: VCV000005122, PMID:11007475, PS1). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 11007475, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.869, 3CNET: 0.925, PP3_P). A missense variant is a common mechanism associated with Immunodeficiency with hyper-IgM (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). A different missense change at the same codon has been reported to be associated with AICDA related disorder (PMID:27577878, PM5_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.94		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.91
MPC		1.9
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.91
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894324; hg19: chr12-8759547; COSMIC: COSV57564670;