22-39015650-T-C

Variant names:

• chr22-39015650-T-C
• rs1569049048
• NM_014508.3:c.73T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014508.3(APOBEC3C):​c.73T>C​(p.Trp25Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APOBEC3C NM_014508.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.61

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]

ENSG00000284554 (HGNC:):

ACMG classification

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=0.033655226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOBEC3C	NM_014508.3	c.73T>C	p.Trp25Arg	missense_variant	Exon 2 of 4	ENST00000361441.5	NP_055323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOBEC3C	ENST00000361441.5	c.73T>C	p.Trp25Arg	missense_variant	Exon 2 of 4	1	NM_014508.3	ENSP00000355340.3
ENSG00000284554	ENST00000381568.9	c.17+1271T>C		intron_variant	Intron 1 of 6	1		ENSP00000370980.4
APOBEC3C	ENST00000428892.1	n.17+1271T>C		intron_variant	Intron 1 of 2	3		ENSP00000390855.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.73T>C (p.W25R) alteration is located in exon 2 (coding exon 2) of the APOBEC3C gene. This alteration results from a T to C substitution at nucleotide position 73, causing the tryptophan (W) at amino acid position 25 to be replaced by an arginine (R). 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	0.15
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.012
DANN	Benign	0.34
DEOGEN2	Benign	0.014	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.00042	N
LIST_S2	Benign	0.034	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.033
Sift	Benign	1.0	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.074
MutPred		0.48		Gain of disorder (P = 0.017);
MVP		0.15
MPC		0.26
ClinPred		0.024	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1569049048; hg19: chr22-39411655;