rs387906329

chr12-8605456-GAGGAAGAGC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM4 PP3 PP5

The NM_020661.4(AICDA):c.177_185del(p.Leu59_Leu62delinsPhe) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L59L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AICDA NM_020661.4 inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.88

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Single-stranded DNA cytosine deaminase (size 197) in uniprot entity AICDA_HUMAN there are 23 pathogenic changes around while only 3 benign (88%) in NM_020661.4
• PM4: Nonframeshift variant in NON repetitive region in NM_020661.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 12-8605456-GAGGAAGAGC-G is Pathogenic according to our data. Variant chr12-8605456-GAGGAAGAGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 5130.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AICDA	NM_020661.4	c.177_185del	p.Leu59_Leu62delinsPhe	inframe_deletion	3/5	ENST00000229335.11
AICDA	NM_001330343.2	c.177_185del	p.Leu59_Leu62delinsPhe	inframe_deletion	3/5
AICDA	NM_001410970.1	c.177_185del	p.Leu59_Leu62delinsPhe	inframe_deletion	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AICDA	ENST00000229335.11	c.177_185del	p.Leu59_Leu62delinsPhe	inframe_deletion	3/5	1	NM_020661.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyper-IgM syndrome type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906329; hg19: chr12-8758052;