22-38961498-A-C

Position:

• chr22-38961498-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145699.4(APOBEC3A):​c.286A>C​(p.Ile96Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000076 in 131,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.0000076 (0 hom., cov: 18)
• Consequence: APOBEC3A NM_145699.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

Genes affected

APOBEC3A (HGNC:17343): (apolipoprotein B mRNA editing enzyme catalytic subunit 3A) This gene is a member of the cytidine deaminase gene family. It is one of seven related genes or pseudogenes 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. The protein encoded by this gene lacks the zinc binding activity of other family members. The protein plays a role in immunity, by restricting transmission of foreign DNA such as viruses. One mechanism of foreign DNA restriction is deamination of foreign double-stranded DNA cytidines to uridines, which leads to DNA degradation. However, other mechanisms are also thought to be involved, as anti-viral effect is not dependent on deaminase activity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12422815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOBEC3A	NM_145699.4	c.286A>C	p.Ile96Leu	missense_variant	3/5	ENST00000249116.7	NP_663745.1
APOBEC3A	NM_001270406.2	c.232A>C	p.Ile78Leu	missense_variant	3/5		NP_001257335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOBEC3A	ENST00000249116.7	c.286A>C	p.Ile96Leu	missense_variant	3/5	1	NM_145699.4	ENSP00000249116.2
APOBEC3A	ENST00000402255.5	c.286A>C	p.Ile96Leu	missense_variant	4/6	5		ENSP00000384359.1

Frequencies

GnomAD3 genomes AF: 0.00000760 AC: 1 AN: 131528 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.0000312

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

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000760 AC: 1 AN: 131528 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 63250

Gnomad4 AFR AF: 0.0000312

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2024

The c.286A>C (p.I96L) alteration is located in exon 3 (coding exon 3) of the APOBEC3A gene. This alteration results from a A to C substitution at nucleotide position 286, causing the isoleucine (I) at amino acid position 96 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.014	T;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.63	.;.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.51	N;N;N
PROVEAN	Benign	-0.91	N;N;.
REVEL	Benign	0.082
Sift	Benign	1.0	T;T;.
Sift4G	Benign	0.18	T;T;T
Polyphen		0.013	B;B;B
Vest4		0.20
MVP		0.43
MPC		3.4
ClinPred		0.16	T
GERP RS		-0.098
Varity_R		0.62
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs902179939; hg19: chr22-39357503;