chr22-38961417-C-T

Position:

chr22-38961417-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4_StrongBP6_ModerateBS2

The NM_145699.4(APOBEC3A):c.205C>T(p.Arg69Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000093 in 1,204,070 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., cov: 18)

Exomes 𝑓: 0.000093 ( 7 hom. )

Failed GnomAD Quality Control

Consequence

APOBEC3A
NM_145699.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.197

Variant links:

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]

APOBEC3A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM1

In a mutagenesis_site Altered deaminase activity and restriction activity towards genetic invaders. (size 0) in uniprot entity ABC3A_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.045476466).

BP6

Variant 22-38961417-C-T is Benign according to our data. Variant chr22-38961417-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2215531.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOBEC3A	NM_145699.4 linkuse as main transcript	c.205C>T	p.Arg69Cys	missense_variant	3/5	ENST00000249116.7	NP_663745.1
APOBEC3A	NM_001270406.2 linkuse as main transcript	c.151C>T	p.Arg51Cys	missense_variant	3/5		NP_001257335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOBEC3A	ENST00000249116.7 linkuse as main transcript	c.205C>T	p.Arg69Cys	missense_variant	3/5	1	NM_145699.4	ENSP00000249116	P1	P31941-1
APOBEC3A	ENST00000402255.5 linkuse as main transcript	c.205C>T	p.Arg69Cys	missense_variant	4/6	5		ENSP00000384359	P1	P31941-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

126628

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00112

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00355

Gnomad NFE

AF:

0.0000488

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000162

AC:

AN:

209734

Hom.:

AF XY:

0.000218

AC XY:

AN XY:

114564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000346

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000803

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000109

Gnomad OTH exome

AF:

0.000191

GnomAD4 exome

AF:

0.0000930

AC:

112

AN:

1204070

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

605894

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000302

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000881

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.0000236

Gnomad4 OTH exome

AF:

0.0000975

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000632

AC:

AN:

126628

Hom.:

Cov.:

AF XY:

0.0000822

AC XY:

AN XY:

60848

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00112

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000488

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000485

Hom.:

ExAC

AF:

0.000184

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.52

CADD

Benign

3.2

DANN

Benign

0.71

DEOGEN2

Benign

0.013

T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.63

.;.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.045

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.23

N;N;N

MutationTaster

Benign

1.0

N;N

PROVEAN

Uncertain

-2.5

D;D;.

REVEL

Benign

0.13

Sift

Benign

0.17

T;T;.

Sift4G

Benign

0.17

T;T;T

Polyphen

0.048

B;B;B

Vest4

0.048

MutPred

0.69

Loss of methylation at R69 (P = 0.0584);Loss of methylation at R69 (P = 0.0584);Loss of methylation at R69 (P = 0.0584);

MVP

0.34

MPC

2.4

ClinPred

0.015

GERP RS

-1.4

Varity_R

0.19

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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