rs11046349

Positions:

• chr12-8604195-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020661.4(AICDA):​c.*89A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,221,676 control chromosomes in the GnomAD database, including 16,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (7162 hom., cov: 31)
  • Exomes 𝑓: 0.10 (9416 hom.)
• Consequence: AICDA NM_020661.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.542

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-8604195-T-G is Benign according to our data. Variant chr12-8604195-T-G is described in ClinVar as [Benign]. Clinvar id is 310575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AICDA	NM_020661.4	c.*89A>C		3_prime_UTR_variant	5/5	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.*89A>C		3_prime_UTR_variant	5/5		NP_001317272.1
AICDA	NM_001410970.1	c.*132A>C		3_prime_UTR_variant	4/4		NP_001397899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AICDA	ENST00000229335.11	c.*89A>C		3_prime_UTR_variant	5/5	1	NM_020661.4	ENSP00000229335	P1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34455 AN: 152008 Hom.: 7122 Cov.: 31

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.0975

Gnomad SAS AF: 0.0708

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0905

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.105 AC: 111992 AN: 1069550 Hom.: 9416 Cov.: 15 AF XY: 0.101 AC XY: 55689 AN XY: 549694

Gnomad4 AFR exome AF: 0.581

Gnomad4 AMR exome AF: 0.0744

Gnomad4 ASJ exome AF: 0.0638

Gnomad4 EAS exome AF: 0.0921

Gnomad4 SAS exome AF: 0.0617

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.0914

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.227 AC: 34555 AN: 152126 Hom.: 7162 Cov.: 31 AF XY: 0.226 AC XY: 16795 AN XY: 74364

Gnomad4 AFR AF: 0.559

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.0672

Gnomad4 EAS AF: 0.0981

Gnomad4 SAS AF: 0.0710

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.0905

Gnomad4 OTH AF: 0.179

Alfa AF: 0.107 Hom.: 1965

Bravo AF: 0.239

Asia WGS AF: 0.123 AC: 428 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Hyper-IgM syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.78

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: rs11046349; hg19: chr12-8756791; COSMIC: COSV57563736; COSMIC: COSV57563736;