Genetic Variant AICDA:c.428-7_428-5delTTT (chr12-8604926-CAAA-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020661.4(AICDA):c.428-7_428-5delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,386,506 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000073 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

AICDA
NM_020661.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.941

Publications

3 publications found

Variant links:

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)

AICDA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
AICDA	NM_020661.4 link	c.428-7_428-5delTTT	splice_region_variant, intron_variant	Intron 3 of 4	ENST00000229335.11	NP_065712.1	Q9GZX7-1Q546Y9Q7Z599
AICDA	NM_001330343.2 link	c.428-37_428-35delTTT	intron_variant	Intron 3 of 4		NP_001317272.1	Q9GZX7-2Q7Z599
AICDA	NM_001410970.1 link	c.427+286_427+288delTTT	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 link	c.428-7_428-5delTTT		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_020661.4	ENSP00000229335.6		Q9GZX7-1

Frequencies

GnomAD3 genomes

AF:

0.00000731

AC:

AN:

136836

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000155

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000240

AC:

AN:

1249670

Hom.:

AF XY:

0.00000482

AC XY:

AN XY:

622910

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29124

American (AMR)

AF:

0.00

AC:

AN:

33050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22258

East Asian (EAS)

AF:

0.00

AC:

AN:

33854

South Asian (SAS)

AF:

0.0000136

AC:

AN:

73714

European-Finnish (FIN)

AF:

0.0000464

AC:

AN:

43108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3618

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

959102

Other (OTH)

AF:

0.00

AC:

AN:

51842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000731

AC:

AN:

136836

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

65504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

36512

American (AMR)

AF:

0.00

AC:

AN:

13632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3350

East Asian (EAS)

AF:

0.00

AC:

AN:

4828

South Asian (SAS)

AF:

0.00

AC:

AN:

4324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

64562

Other (OTH)

AF:

0.00

AC:

AN:

1856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.94

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over