chr12-8603148-T-C

Position:

• chr12-8603148-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000229335.11(AICDA):​c.*1136A>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 0.0301 in 148,720 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (97 hom., cov: 29)
  • Exomes 𝑓: 0.0029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AICDA ENST00000229335.11 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.354

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0301 (4483/148720) while in subpopulation AFR AF= 0.0491 (1991/40562). AF 95% confidence interval is 0.0473. There are 97 homozygotes in gnomad4. There are 2099 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 97 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AICDA	NM_020661.4	c.*1136A>G		3_prime_UTR_variant	5/5	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.*1136A>G		3_prime_UTR_variant	5/5		NP_001317272.1
AICDA	NM_001410970.1	c.*1179A>G		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.*1136A>G		3_prime_UTR_variant	5/5	1	NM_020661.4	ENSP00000229335	P1

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4487 AN: 148626 Hom.: 97 Cov.: 29

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.0474

Gnomad EAS AF: 0.000586

Gnomad SAS AF: 0.00868

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.0377

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00286 AC: 1 AN: 350 Hom.: 0 Cov.: 0 AF XY: 0.00376 AC XY: 1 AN XY: 266

Gnomad4 AFR exome AF: 0.250

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: 0.0301 AC: 4483 AN: 148720 Hom.: 97 Cov.: 29 AF XY: 0.0289 AC XY: 2099 AN XY: 72602

Gnomad4 AFR AF: 0.0491

Gnomad4 AMR AF: 0.0306

Gnomad4 ASJ AF: 0.0474

Gnomad4 EAS AF: 0.000587

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.0237

Gnomad4 OTH AF: 0.0373

Alfa AF: 0.0280 Hom.: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 2 Uncertain:1

Uncertain significance, 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, 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.7
DANN	Benign	0.51

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: rs371020938; hg19: chr12-8755744;