12-8605227-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_020661.4(AICDA):​c.415A>C​(p.Met139Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M139T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

AICDA
NM_020661.4 missense

Scores

11
6
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.45
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a chain Single-stranded DNA cytosine deaminase (size 197) in uniprot entity AICDA_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_020661.4
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 Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AICDANM_020661.4 linkc.415A>C p.Met139Leu missense_variant Exon 3 of 5 ENST00000229335.11 NP_065712.1 Q9GZX7-1Q546Y9Q7Z599
AICDANM_001330343.2 linkc.415A>C p.Met139Leu missense_variant Exon 3 of 5 NP_001317272.1 Q9GZX7-2Q7Z599
AICDANM_001410970.1 linkc.415A>C p.Met139Leu missense_variant Exon 3 of 4 NP_001397899.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AICDAENST00000229335.11 linkc.415A>C p.Met139Leu missense_variant Exon 3 of 5 1 NM_020661.4 ENSP00000229335.6 Q9GZX7-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461726
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.51
D;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.076
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.21
D
MutationAssessor
Pathogenic
3.7
H;H
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-2.7
D;D
REVEL
Uncertain
0.63
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.93
P;.
Vest4
0.85
MutPred
0.94
Loss of MoRF binding (P = 0.0924);Loss of MoRF binding (P = 0.0924);
MVP
0.83
MPC
1.3
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.96
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-8757823; API