22-39025233-A-C

Variant names:

• chr22-39025233-A-C
• rs778365707
• NM_152426.4:c.374A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152426.4(APOBEC3D):​c.374A>C​(p.Asn125Thr) 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 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign 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. N125S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APOBEC3D NM_152426.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68
• Publications: 0 publications found

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]

ENSG00000284554 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152426.4. 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
	APOBEC3D	NM_152426.4	MANE Select	c.374A>C	p.Asn125Thr	missense	Exon 3 of 7	NP_689639.2	Q96AK3
	APOBEC3D	NM_001363781.1		c.210+2219A>C		intron	N/A	NP_001350710.1	Q6ICH2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOBEC3D	ENST00000216099.13	TSL:2 MANE Select	c.374A>C	p.Asn125Thr	missense	Exon 3 of 7	ENSP00000216099.7	Q96AK3
	ENSG00000284554	ENST00000381568.9	TSL:1	c.374A>C	p.Asn125Thr	missense	Exon 3 of 7	ENSP00000370980.4
	APOBEC3D	ENST00000427494.6	TSL:1	c.210+2219A>C		intron	N/A	ENSP00000388017.2	Q6ICH2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151888 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251400 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151888 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74174

African (AFR) AF: 0.0000484 AC: 2 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67924

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.7
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.16
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.67		Gain of glycosylation at N125 (P = 0.0545)
MVP		0.45
MPC		0.33
ClinPred		0.36	T
GERP RS		1.2
Varity_R		0.11
gMVP		0.14
Mutation Taster		=94/6	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: rs778365707; hg19: chr22-39421238;