12-8603195-G-A

Position:

• chr12-8603195-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020661.4(AICDA):​c.*1089C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 146,588 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (4 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AICDA NM_020661.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.976

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-8603195-G-A is Benign according to our data. Variant chr12-8603195-G-A is described in ClinVar as [Benign]. Clinvar id is 310561.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00153 (224/146588) while in subpopulation EAS AF= 0.0342 (171/4998). AF 95% confidence interval is 0.03. There are 4 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AICDA	NM_020661.4	c.*1089C>T		3_prime_UTR_variant	5/5	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.*1089C>T		3_prime_UTR_variant	5/5		NP_001317272.1
AICDA	NM_001410970.1	c.*1132C>T		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.*1089C>T		3_prime_UTR_variant	5/5	1	NM_020661.4	ENSP00000229335	P1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 224 AN: 146512 Hom.: 4 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000206

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.00930

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000448

Gnomad OTH AF: 0.00201

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 44 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 30

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.00153 AC: 224 AN: 146588 Hom.: 4 Cov.: 29 AF XY: 0.00177 AC XY: 126 AN XY: 71048

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000206

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.00934

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000448

Gnomad4 OTH AF: 0.00199

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.00189

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgM syndrome type 2 Benign:1

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 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	-0.94
CADD	Benign	1.1
DANN	Benign	0.47

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: rs141460280; hg19: chr12-8755791;