Genetic Variant APOBEC3C:p.Tyr86Asn (chr22-39017847-T-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_014508.3(APOBEC3C):c.256T>A(p.Tyr86Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

APOBEC3C
NM_014508.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.70

Variant links:

Genes affected

APOBEC3C (HGNC:17353): (apolipoprotein B mRNA editing enzyme catalytic subunit 3C) 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. It is thought that the proteins may be RNA editing enzymes and have roles in growth or cell cycle control. [provided by RefSeq, Jul 2008]

APOBEC3C links:

ENSG00000284554 (HGNC:):

ENSG00000284554 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a mutagenesis_site Resistant to HIV-1 Vif and abolishes Vif binding. (size 0) in uniprot entity ABC3C_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOBEC3C	NM_014508.3 link	c.256T>A	p.Tyr86Asn	missense_variant	Exon 3 of 4	ENST00000361441.5	NP_055323.2	Q9NRW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOBEC3C	ENST00000361441.5 link	c.256T>A	p.Tyr86Asn	missense_variant	Exon 3 of 4	1	NM_014508.3	ENSP00000355340.3	Q9NRW3
ENSG00000284554	ENST00000381568.9 link	c.17+3468T>A		intron_variant	Intron 1 of 6	1		ENSP00000370980.4
APOBEC3C	ENST00000428892.1 link	n.99T>A		non_coding_transcript_exon_variant	Exon 2 of 3	3		ENSP00000390855.1	F8WB92

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251486

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS 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:

0.00000410

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.256T>A (p.Y86N) alteration is located in exon 3 (coding exon 3) of the APOBEC3C gene. This alteration results from a T to A substitution at nucleotide position 256, causing the tyrosine (Y) at amino acid position 86 to be replaced by an asparagine (N). 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

Uncertain

0.52

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.30

Eigen

Benign

0.18

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.046

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.3

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-7.7

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.83

MutPred

0.78

Gain of ubiquitination at K85 (P = 0.0737);

MVP

0.84

MPC

0.84

ClinPred

0.75

GERP RS

2.0

Varity_R

0.81

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over