Genetic Variant APOBEC3C:p.His66Asn (chr22-39017787-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014508.3(APOBEC3C):c.196C>A(p.His66Asn) 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 1,461,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. H66Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

APOBEC3C
NM_014508.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.15

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014508.3. 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
	APOBEC3C	NM_014508.3	MANE Select	c.196C>A	p.His66Asn	missense	Exon 3 of 4	NP_055323.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOBEC3C	ENST00000361441.5	TSL:1 MANE Select	c.196C>A	p.His66Asn	missense	Exon 3 of 4	ENSP00000355340.3	Q9NRW3
ENSG00000284554	ENST00000381568.9	TSL:1	c.17+3408C>A		intron	N/A	ENSP00000370980.4
APOBEC3C	ENST00000869067.1		c.175-186C>A		intron	N/A	ENSP00000539126.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461342

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111558

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.33

Eigen

Benign

0.16

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

PhyloP100

3.2

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.6

REVEL

Uncertain

0.64

Sift

Uncertain

0.019

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.80

MutPred

0.97

Loss of catalytic residue at H66 (P = 0.0492)

MVP

0.96

MPC

0.67

ClinPred

0.97

GERP RS

2.0

Varity_R

0.53

gMVP

0.55

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over