rs104894324

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.09

Publications

10 publications found

Variant links:

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]

AICDA Gene-Disease associations (from GenCC):

hyper-IgM syndrome type 2
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

AICDA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

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 VariationId is 863582.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.3381 (below the threshold of 3.09). Trascript score misZ: 0.98605 (below the threshold of 3.09). GenCC associations: The gene is linked to hyper-IgM syndrome type 2.

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 VariationId is 5122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AICDA	NM_020661.4 link	c.70C>T	p.Arg24Trp	missense_variant	Exon 2 of 5	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2 link	c.70C>T	p.Arg24Trp	missense_variant	Exon 2 of 5		NP_001317272.1
AICDA	NM_001410970.1 link	c.70C>T	p.Arg24Trp	missense_variant	Exon 2 of 4		NP_001397899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AICDA	ENST00000229335.11 link	c.70C>T	p.Arg24Trp	missense_variant	Exon 2 of 5	1	NM_020661.4	ENSP00000229335.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249542

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111998

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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:3

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is present in population databases (rs104894324, gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive hyper Ig M syndrome (PMID: 11007475, 26551569). ClinVar contains an entry for this variant (Variation ID: 5122). 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. Experimental studies have shown that this missense change affects AICDA function (PMID: 22715099). 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. For these reasons, this variant has been classified as Pathogenic. -

Sep 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 03, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

5.1

PrimateAI

Pathogenic

0.81

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

GERP RS

4.4

PromoterAI

0.0060

Neutral

(source)

Varity_R

0.91

gMVP

0.89

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over