chr12-8604195-T-G

Variant names:

• chr12-8604195-T-G
• rs11046349
• NM_020661.4:c.*89A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
AICDA	NM_020661.4	c.*89A>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.*89A>C		3_prime_UTR_variant	Exon 5 of 5		NP_001317272.1
AICDA	NM_001410970.1	c.*132A>C		3_prime_UTR_variant	Exon 4 of 4		NP_001397899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AICDA	ENST00000229335.11	c.*89A>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_020661.4	ENSP00000229335.6

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

African (AFR) AF: 0.581 AC: 15087 AN: 25950

American (AMR) AF: 0.0744 AC: 3264 AN: 43894

Ashkenazi Jewish (ASJ) AF: 0.0638 AC: 1507 AN: 23626

East Asian (EAS) AF: 0.0921 AC: 3482 AN: 37816

South Asian (SAS) AF: 0.0617 AC: 4816 AN: 78112

European-Finnish (FIN) AF: 0.160 AC: 8400 AN: 52602

Middle Eastern (MID) AF: 0.145 AC: 728 AN: 5024

European-Non Finnish (NFE) AF: 0.0914 AC: 68995 AN: 755072

Other (OTH) AF: 0.120 AC: 5713 AN: 47454

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

African (AFR) AF: 0.559 AC: 23157 AN: 41462

American (AMR) AF: 0.119 AC: 1815 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 233 AN: 3466

East Asian (EAS) AF: 0.0981 AC: 509 AN: 5186

South Asian (SAS) AF: 0.0710 AC: 343 AN: 4828

European-Finnish (FIN) AF: 0.177 AC: 1870 AN: 10590

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0905 AC: 6157 AN: 68010

Other (OTH) AF: 0.179 AC: 378 AN: 2110

Alfa AF: 0.110 Hom.: 2441

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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