12-8604885-G-T

Variant names:

• chr12-8604885-G-T
• rs2028373
• NM_020661.4:c.465C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_020661.4(AICDA):​c.465C>A​(p.His155Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,610,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H155R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AICDA NM_020661.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.164
• Publications: 29 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.3381 (below the threshold of 3.09). Trascript score misZ: 0.98605 (below the threshold of 3.09). GenCC associations: The gene is linked to hyper-IgM syndrome type 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.030617386).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020661.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AICDA	NM_020661.4	MANE Select	c.465C>A	p.His155Gln	missense	Exon 4 of 5	NP_065712.1	Q9GZX7-1
	AICDA	NM_001330343.2		c.435C>A	p.His145Gln	missense	Exon 4 of 5	NP_001317272.1	Q9GZX7-2
	AICDA	NM_001410970.1		c.427+330C>A		intron	N/A	NP_001397899.1	Q6QJ80

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AICDA	ENST00000229335.11	TSL:1 MANE Select	c.465C>A	p.His155Gln	missense	Exon 4 of 5	ENSP00000229335.6	Q9GZX7-1
	AICDA	ENST00000543081.6	TSL:1	c.427+330C>A		intron	N/A	ENSP00000439103.2	Q6QJ80
	AICDA	ENST00000544516.6	TSL:1	c.157-548C>A		intron	N/A	ENSP00000439538.2	Q6QLN7

Frequencies

GnomAD3 genomes AF: 0.00000670 AC: 1 AN: 149230 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000247

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461038 Hom.: 0 Cov.: 66 AF XY: 0.00 AC XY: 0 AN XY: 726810

African (AFR) AF: 0.0000599 AC: 2 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome AF: 0.00000670 AC: 1 AN: 149230 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 72536

African (AFR) AF: 0.0000247 AC: 1 AN: 40488

American (AMR) AF: 0.00 AC: 0 AN: 15010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5056

South Asian (SAS) AF: 0.00 AC: 0 AN: 4740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67608

Other (OTH) AF: 0.00 AC: 0 AN: 2036

Alfa AF: 0.00 Hom.: 96971

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hyper-IgM syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.12
DANN	Benign	0.34
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.8	N
PhyloP100		-0.16
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.34		Loss of ubiquitination at K160 (P = 0.0877)
MVP		0.56
MPC		0.80
ClinPred		0.22	T
GERP RS		-0.24
Varity_R		0.14
gMVP		0.25
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs2028373; hg19: chr12-8757481;