22-39025649-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152426.4(APOBEC3D):​c.583C>T​(p.Arg195Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

APOBEC3D
NM_152426.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.03
Variant links:
Genes affected
APOBEC3D (HGNC:17354): (apolipoprotein B mRNA editing enzyme catalytic subunit 3D) This gene is a member of the cytidine deaminase gene family. It is one of a group of related genes found in a cluster, thought to result from gene duplication, on chromosome 22. Members of the cluster encode proteins that are structurally and functionally related to the C to U RNA-editing cytidine deaminase APOBEC1 and inhibit retroviruses, such as HIV, by deaminating cytosine residues in nascent retroviral cDNA. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.028859675).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APOBEC3DNM_152426.4 linkc.583C>T p.Arg195Cys missense_variant Exon 4 of 7 ENST00000216099.13 NP_689639.2 B2CML4
APOBEC3DXM_017028596.3 linkc.790C>T p.Arg264Cys missense_variant Exon 3 of 6 XP_016884085.1
APOBEC3DXM_047441142.1 linkc.583C>T p.Arg195Cys missense_variant Exon 4 of 5 XP_047297098.1
APOBEC3DNM_001363781.1 linkc.210+2635C>T intron_variant Intron 2 of 3 NP_001350710.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APOBEC3DENST00000216099.13 linkc.583C>T p.Arg195Cys missense_variant Exon 4 of 7 2 NM_152426.4 ENSP00000216099.7 Q96AK3
ENSG00000284554ENST00000381568.9 linkc.583C>T p.Arg195Cys missense_variant Exon 4 of 7 1 ENSP00000370980.4
APOBEC3DENST00000427494.6 linkc.210+2635C>T intron_variant Intron 2 of 3 1 ENSP00000388017.2 Q6ICH2
APOBEC3DENST00000622217.3 linkc.18-3714C>T intron_variant Intron 1 of 3 5 ENSP00000480718.3 A0A087WX48

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152124
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251462
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000301
AC:
44
AN:
1461870
Hom.:
0
Cov.:
34
AF XY:
0.0000206
AC XY:
15
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000324
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152124
Hom.:
0
Cov.:
31
AF XY:
0.0000404
AC XY:
3
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.0000725
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000567
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 11, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.583C>T (p.R195C) alteration is located in exon 4 (coding exon 4) of the APOBEC3D gene. This alteration results from a C to T substitution at nucleotide position 583, causing the arginine (R) at amino acid position 195 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
0.0020
DANN
Benign
0.63
DEOGEN2
Benign
0.039
.;T
Eigen
Benign
-2.0
Eigen_PC
Benign
-2.2
FATHMM_MKL
Benign
0.0016
N
LIST_S2
Benign
0.42
T;.
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.029
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.97
.;L
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.090
Sift
Benign
0.19
T;T
Sift4G
Benign
0.21
T;T
Polyphen
0.0
.;B
Vest4
0.059
MutPred
0.39
Gain of ubiquitination at K198 (P = 0.0632);Gain of ubiquitination at K198 (P = 0.0632);
MVP
0.095
MPC
0.062
ClinPred
0.021
T
GERP RS
-4.9
Varity_R
0.042
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.19
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs746506547; hg19: chr22-39421654; COSMIC: COSV53325418; API