Genetic Variant NM_203454.3:c.1033G>A (chr1-183647749-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_203454.3(APOBEC4):c.1033G>A(p.Val345Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 1,613,802 control chromosomes in the GnomAD database, including 2,030 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.069 ( 626 hom., cov: 33)

Exomes 𝑓: 0.035 ( 1404 hom. )

Consequence

APOBEC4
NM_203454.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.238

Publications

29 publications found

Variant links:

Genes affected

APOBEC4 (HGNC:32152): (apolipoprotein B mRNA editing enzyme catalytic polypeptide like 4) This gene encodes a member of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases, which convert cytidine to uridine. Other AID/APOBEC family members are involved in mRNA editing, somatic hypermutation and recombination of immunoglobulin genes, and innate immunity to retroviral infection. [provided by RefSeq, Jul 2008]

APOBEC4 links:

RGL1 (HGNC:30281): (ral guanine nucleotide dissociation stimulator like 1) Predicted to be involved in regulation of catalytic activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

RGL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025907457).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203454.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APOBEC4	NM_203454.3	MANE Select	c.1033G>A	p.Val345Met	missense	Exon 2 of 2	NP_982279.1
RGL1	NM_015149.6		c.-33+11248C>T		intron	N/A	NP_055964.3
RGL1	NM_001297669.3		c.-143+11248C>T		intron	N/A	NP_001284598.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APOBEC4	ENST00000308641.6	TSL:1 MANE Select	c.1033G>A	p.Val345Met	missense	Exon 2 of 2	ENSP00000310622.4
RGL1	ENST00000304685.8	TSL:1	c.-33+11248C>T		intron	N/A	ENSP00000303192.3
APOBEC4	ENST00000481562.1	TSL:3	n.294G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0685

AC:

10417

AN:

152108

Hom.:

620

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0347

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.0803

Gnomad SAS

AF:

0.0627

Gnomad FIN

AF:

0.0262

Gnomad MID

AF:

0.0446

Gnomad NFE

AF:

0.0287

Gnomad OTH

AF:

0.0602

GnomAD2 exomes

AF:

0.0434

AC:

10896

AN:

251340

AF XY:

0.0429

show subpopulations

Gnomad AFR exome

AF:

0.165

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.0830

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.0279

Gnomad OTH exome

AF:

0.0356

GnomAD4 exome

AF:

0.0348

AC:

50922

AN:

1461576

Hom.:

1404

Cov.:

AF XY:

0.0354

AC XY:

25703

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.171

AC:

5719

AN:

33458

American (AMR)

AF:

0.0182

AC:

814

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

353

AN:

26124

East Asian (EAS)

AF:

0.0450

AC:

1788

AN:

39690

South Asian (SAS)

AF:

0.0661

AC:

5696

AN:

86234

European-Finnish (FIN)

AF:

0.0265

AC:

1416

AN:

53416

Middle Eastern (MID)

AF:

0.0480

AC:

277

AN:

5768

European-Non Finnish (NFE)

AF:

0.0291

AC:

32332

AN:

1111796

Other (OTH)

AF:

0.0419

AC:

2527

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

2690

5380

8070

10760

13450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1366

2732

4098

5464

6830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0686

AC:

10438

AN:

152226

Hom.:

626

Cov.:

AF XY:

0.0675

AC XY:

5022

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.163

AC:

6760

AN:

41508

American (AMR)

AF:

0.0347

AC:

531

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3470

East Asian (EAS)

AF:

0.0809

AC:

419

AN:

5178

South Asian (SAS)

AF:

0.0629

AC:

304

AN:

4830

European-Finnish (FIN)

AF:

0.0262

AC:

278

AN:

10606

Middle Eastern (MID)

AF:

0.0411

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0287

AC:

1954

AN:

68008

Other (OTH)

AF:

0.0591

AC:

125

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

460

919

1379

1838

2298

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0389

Hom.:

752

Bravo

AF:

0.0732

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0278

AC:

107

ESP6500AA

AF:

0.152

AC:

668

ESP6500EA

AF:

0.0281

AC:

242

ExAC

AF:

0.0460

AC:

5588

Asia WGS

AF:

0.0720

AC:

252

AN:

3478

EpiCase

AF:

0.0303

EpiControl

AF:

0.0286

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.9

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.029

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.24

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.2

REVEL

Benign

0.14

Sift

Uncertain

0.016

Sift4G

Uncertain

0.032

Polyphen

0.088

Vest4

0.047

MPC

0.12

ClinPred

0.0027

GERP RS

3.3

Varity_R

0.11

gMVP

0.13

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over