chr12-8603146-T-C

Variant names:

• chr12-8603146-T-C
• rs7138990
• NM_020661.4:c.*1138A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020661.4(AICDA):​c.*1138A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 130,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AICDA NM_020661.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.625
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AICDA	NM_020661.4	c.*1138A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.*1138A>G		3_prime_UTR_variant	Exon 5 of 5		NP_001317272.1
AICDA	NM_001410970.1	c.*1181A>G		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.*1138A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_020661.4	ENSP00000229335.6

Frequencies

GnomAD3 genomes AF: 0.000529 AC: 69 AN: 130468 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000362

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000588

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00376

Gnomad NFE AF: 0.000374

Gnomad OTH AF: 0.00111

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 304 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 236

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 18

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 264

Other (OTH) AF: 0.00 AC: 0 AN: 10

GnomAD4 genome AF: 0.000521 AC: 68 AN: 130518 Hom.: 0 Cov.: 28 AF XY: 0.000423 AC XY: 27 AN XY: 63846

African (AFR) AF: 0.00102 AC: 28 AN: 27346

American (AMR) AF: 0.000361 AC: 5 AN: 13846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3194

East Asian (EAS) AF: 0.000589 AC: 3 AN: 5092

South Asian (SAS) AF: 0.00113 AC: 5 AN: 4436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9430

Middle Eastern (MID) AF: 0.00400 AC: 1 AN: 250

European-Non Finnish (NFE) AF: 0.000374 AC: 24 AN: 64204

Other (OTH) AF: 0.00110 AC: 2 AN: 1820

Alfa AF: 0.000754 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgM syndrome type 2 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.50
PhyloP100		0.63

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: rs7138990; hg19: chr12-8755742;