NM_020661.4:c.428-5delT

Variant names:

• chr12-8604926-CA-C
• rs5796316
• NM_020661.4:c.428-5delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_020661.4(AICDA):​c.428-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,372,598 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: AICDA NM_020661.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.227
• Publications: 3 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 -10 ACMG points.

• BP6: Variant 12-8604926-CA-C is Benign according to our data. Variant chr12-8604926-CA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1091711.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00294 (402/136798) while in subpopulation AFR AF = 0.0107 (392/36570). AF 95% confidence interval is 0.00984. There are 2 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AICDA	NM_020661.4	c.428-5delT		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000229335.11	NP_065712.1
AICDA	NM_001330343.2	c.428-35delT		intron_variant	Intron 3 of 4		NP_001317272.1
AICDA	NM_001410970.1	c.427+288delT		intron_variant	Intron 3 of 3		NP_001397899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AICDA	ENST00000229335.11	c.428-5delT		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_020661.4	ENSP00000229335.6

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 403 AN: 136802 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000608

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00108

GnomAD2 exomes AF: 0.00896 AC: 1321 AN: 147494 AF XY: 0.00816

Gnomad AFR exome AF: 0.0456

Gnomad AMR exome AF: 0.00996

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.00595

Gnomad FIN exome AF: 0.00401

Gnomad NFE exome AF: 0.00639

Gnomad OTH exome AF: 0.00631

GnomAD4 exome AF: 0.00127 AC: 1571 AN: 1235800 Hom.: 1 Cov.: 34 AF XY: 0.00121 AC XY: 747 AN XY: 615628

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0207 AC: 582 AN: 28106

American (AMR) AF: 0.00632 AC: 205 AN: 32432

Ashkenazi Jewish (ASJ) AF: 0.00160 AC: 35 AN: 21938

East Asian (EAS) AF: 0.00105 AC: 35 AN: 33446

South Asian (SAS) AF: 0.00215 AC: 156 AN: 72656

European-Finnish (FIN) AF: 0.00153 AC: 65 AN: 42478

Middle Eastern (MID) AF: 0.00196 AC: 7 AN: 3576

European-Non Finnish (NFE) AF: 0.000442 AC: 420 AN: 949990

Other (OTH) AF: 0.00129 AC: 66 AN: 51178

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00294 AC: 402 AN: 136798 Hom.: 2 Cov.: 0 AF XY: 0.00287 AC XY: 188 AN XY: 65504

African (AFR) AF: 0.0107 AC: 392 AN: 36570

American (AMR) AF: 0.000293 AC: 4 AN: 13638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3350

East Asian (EAS) AF: 0.00 AC: 0 AN: 4812

South Asian (SAS) AF: 0.00 AC: 0 AN: 4298

European-Finnish (FIN) AF: 0.000608 AC: 4 AN: 6576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64530

Other (OTH) AF: 0.00108 AC: 2 AN: 1860

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgM syndrome type 2 Benign:1

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs5796316; hg19: chr12-8757522;