Genetic Variant NM_020661.4:c.428-6_428-5dupTT (chr12-8604926-C-CAA) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_020661.4(AICDA):c.428-6_428-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0926 in 1,175,124 control chromosomes in the GnomAD database, including 83 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.017 ( 49 hom., cov: 0)

Exomes 𝑓: 0.10 ( 34 hom. )

Consequence

AICDA
NM_020661.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.227

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: Benign. The variant received -9 ACMG points.

BP6

Variant 12-8604926-C-CAA is Benign according to our data. Variant chr12-8604926-C-CAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 310579.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
AICDA	NM_020661.4 link	c.428-6_428-5dupTT	splice_region_variant, intron_variant	Intron 3 of 4	ENST00000229335.11	NP_065712.1	Q9GZX7-1Q546Y9Q7Z599
AICDA	NM_001330343.2 link	c.428-36_428-35dupTT	intron_variant	Intron 3 of 4		NP_001317272.1	Q9GZX7-2Q7Z599
AICDA	NM_001410970.1 link	c.427+287_427+288dupTT	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.428-6_428-5dupTT		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_020661.4	ENSP00000229335.6		Q9GZX7-1

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2358

AN:

136716

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00778

Gnomad AMI

AF:

0.00224

Gnomad AMR

AF:

0.0545

Gnomad ASJ

AF:

0.0263

Gnomad EAS

AF:

0.00228

Gnomad SAS

AF:

0.0194

Gnomad FIN

AF:

0.0246

Gnomad MID

AF:

0.0169

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.0151

GnomAD2 exomes

AF:

0.0626

AC:

9227

AN:

147494

AF XY:

0.0607

show subpopulations

Gnomad AFR exome

AF:

0.0253

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.0699

Gnomad EAS exome

AF:

0.0438

Gnomad FIN exome

AF:

0.0702

Gnomad NFE exome

AF:

0.0517

Gnomad OTH exome

AF:

0.0618

GnomAD4 exome

AF:

0.103

AC:

106472

AN:

1038412

Hom.:

Cov.:

AF XY:

0.100

AC XY:

52191

AN XY:

520326

show subpopulations

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

African (AFR)

AF:

0.0421

AC:

1143

AN:

27130

American (AMR)

AF:

0.131

AC:

4062

AN:

31078

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

2052

AN:

19580

East Asian (EAS)

AF:

0.0868

AC:

2615

AN:

30116

South Asian (SAS)

AF:

0.0733

AC:

4838

AN:

66028

European-Finnish (FIN)

AF:

0.0995

AC:

3908

AN:

39282

Middle Eastern (MID)

AF:

0.100

AC:

319

AN:

3180

European-Non Finnish (NFE)

AF:

0.107

AC:

83041

AN:

777910

Other (OTH)

AF:

0.102

AC:

4494

AN:

44108

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.270

Heterozygous variant carriers

13075

26151

39226

52302

65377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3218

6436

9654

12872

16090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0173

AC:

2360

AN:

136712

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1201

AN XY:

65458

show subpopulations

African (AFR)

AF:

0.00777

AC:

284

AN:

36554

American (AMR)

AF:

0.0545

AC:

743

AN:

13622

Ashkenazi Jewish (ASJ)

AF:

0.0263

AC:

AN:

3350

East Asian (EAS)

AF:

0.00229

AC:

AN:

4806

South Asian (SAS)

AF:

0.0195

AC:

AN:

4298

European-Finnish (FIN)

AF:

0.0246

AC:

162

AN:

6574

Middle Eastern (MID)

AF:

0.0184

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0148

AC:

953

AN:

64484

Other (OTH)

AF:

0.0151

AC:

AN:

1860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

102

203

305

406

508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperimmunoglobulin M syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyper-IgM syndrome type 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 20, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over