Genetic Variant NM_020661.4:c.428-7_428-5dupTTT (chr12-8604926-C-CAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_020661.4(AICDA):c.428-7_428-5dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,383,320 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

AICDA
NM_020661.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0000804

AC:

AN:

136810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000274

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000734

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00129

AC:

190

AN:

147494

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.000446

Gnomad AMR exome

AF:

0.00253

Gnomad ASJ exome

AF:

0.000751

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.000835

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000343

AC:

428

AN:

1246514

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

243

AN XY:

621404

show subpopulations

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

African (AFR)

AF:

0.000172

AC:

AN:

29102

American (AMR)

AF:

0.00258

AC:

AN:

32946

Ashkenazi Jewish (ASJ)

AF:

0.000361

AC:

AN:

22186

East Asian (EAS)

AF:

0.0000889

AC:

AN:

33742

South Asian (SAS)

AF:

0.00171

AC:

126

AN:

73526

European-Finnish (FIN)

AF:

0.000768

AC:

AN:

42952

Middle Eastern (MID)

AF:

0.000554

AC:

AN:

3610

European-Non Finnish (NFE)

AF:

0.000146

AC:

140

AN:

956750

Other (OTH)

AF:

0.000503

AC:

AN:

51700

⚠️ 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: 0.284

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000804

AC:

AN:

136806

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

65510

show subpopulations

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

African (AFR)

AF:

0.0000273

AC:

AN:

36570

American (AMR)

AF:

0.0000733

AC:

AN:

13644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3350

East Asian (EAS)

AF:

0.00

AC:

AN:

4812

South Asian (SAS)

AF:

0.00209

AC:

AN:

4298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64524

Other (OTH)

AF:

0.00

AC:

AN:

1860

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000768129), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.393

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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.23

Mutation Taster

=100/0

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over