12-8603145-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_020661.4(AICDA):c.*1139A>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 0.00303 in 147,618 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AICDA NM_020661.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.22

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 12-8603145-T-C is Benign according to our data. Variant chr12-8603145-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 310557.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00303 (448/147618) while in subpopulation AFR AF= 0.0097 (392/40430). AF 95% confidence interval is 0.0089. There are 1 homozygotes in gnomad4. There are 218 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AICDA	NM_020661.4	c.*1139A>G		3_prime_UTR_variant	5/5	ENST00000229335.11
AICDA	NM_001330343.2	c.*1139A>G		3_prime_UTR_variant	5/5
AICDA	NM_001410970.1	c.*1182A>G		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AICDA	ENST00000229335.11	c.*1139A>G		3_prime_UTR_variant	5/5	1	NM_020661.4	P1

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 448 AN: 147520 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00127

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000783

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.000321

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000376

Gnomad OTH AF: 0.00150

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 268 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00303 AC: 448 AN: 147618 Hom.: 1 Cov.: 30 AF XY: 0.00303 AC XY: 218 AN XY: 71952

Gnomad4 AFR AF: 0.00970

Gnomad4 AMR AF: 0.00127

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000785

Gnomad4 SAS AF: 0.000214

Gnomad4 FIN AF: 0.000321

Gnomad4 NFE AF: 0.000376

Gnomad4 OTH AF: 0.00149

Alfa AF: 0.00203 Hom.: 0

Bravo AF: 0.00332

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgM syndrome type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	1.4
Dann	Benign	0.081

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: rs773190855; hg19: chr12-8755741;