chr12-8605227-T-C

Variant names:

• chr12-8605227-T-C
• rs104894322
• NM_020661.4:c.415A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_020661.4(AICDA):​c.415A>G​(p.Met139Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M139T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AICDA NM_020661.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.45
• Publications: 8 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: Pathogenic. The variant received 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-8605226-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 636339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 12-8605227-T-C is Pathogenic according to our data. Variant chr12-8605227-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 5126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.415A>G	p.Met139Val	missense	Exon 3 of 5	NP_065712.1	Q9GZX7-1
	AICDA	NM_001330343.2		c.415A>G	p.Met139Val	missense	Exon 3 of 5	NP_001317272.1	Q9GZX7-2
	AICDA	NM_001410970.1		c.415A>G	p.Met139Val	missense	Exon 3 of 4	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.415A>G	p.Met139Val	missense	Exon 3 of 5	ENSP00000229335.6	Q9GZX7-1
	AICDA	ENST00000543081.6	TSL:1	c.415A>G	p.Met139Val	missense	Exon 3 of 4	ENSP00000439103.2	Q6QJ80
	AICDA	ENST00000544516.6	TSL:1	c.157-890A>G		intron	N/A	ENSP00000439538.2	Q6QLN7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hyper-IgM syndrome type 2 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.4
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.94
MutPred		0.96		Loss of MoRF binding (P = 0.0976)
MVP		0.87
MPC		1.8
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.88
Mutation Taster		=13/87	disease causing (ClinVar)

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: rs104894322; hg19: chr12-8757823;