22-39018327-G-C

Variant names:

• chr22-39018327-G-C
• NM_014508.3:c.513G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014508.3(APOBEC3C):​c.513G>C​(p.Trp171Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 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: 6.8e-7 (0 hom.)
• Consequence: APOBEC3C NM_014508.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOBEC3C	NM_014508.3	c.513G>C	p.Trp171Cys	missense_variant	Exon 4 of 4	ENST00000361441.5	NP_055323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOBEC3C	ENST00000361441.5	c.513G>C	p.Trp171Cys	missense_variant	Exon 4 of 4	1	NM_014508.3	ENSP00000355340.3
ENSG00000284554	ENST00000381568.9	c.17+3948G>C		intron_variant	Intron 1 of 6	1		ENSP00000370980.4
APOBEC3C	ENST00000428892.1	n.*170G>C		non_coding_transcript_exon_variant	Exon 3 of 3	3		ENSP00000390855.1
APOBEC3C	ENST00000428892.1	n.*170G>C		3_prime_UTR_variant	Exon 3 of 3	3		ENSP00000390855.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

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: 0.00

GnomAD4 genome Cov.: 31

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.513G>C (p.W171C) alteration is located in exon 4 (coding exon 4) of the APOBEC3C gene. This alteration results from a G to C substitution at nucleotide position 513, causing the tryptophan (W) at amino acid position 171 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	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-12	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.85		Gain of catalytic residue at P170 (P = 0.0073);
MVP		0.87
MPC		0.82
ClinPred		1.0	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-39414332;