Genetic Variant NM_203454.3:c.961A>G (chr1-183647821-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_203454.3(APOBEC4):c.961A>G(p.Asn321Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00244 in 1,614,220 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 49 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 46 hom. )

Consequence

APOBEC4
NM_203454.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.36

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003106892).

BP6

Variant 1-183647821-T-C is Benign according to our data. Variant chr1-183647821-T-C is described in ClinVar as Benign. ClinVar VariationId is 783956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1983/152330) while in subpopulation AFR AF = 0.0457 (1900/41568). AF 95% confidence interval is 0.044. There are 49 homozygotes in GnomAd4. There are 913 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 49 AR gene

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	UniProt
APOBEC4	NM_203454.3	MANE Select	c.961A>G	p.Asn321Asp	missense	Exon 2 of 2	NP_982279.1	Q8WW27
RGL1	NM_015149.6		c.-33+11320T>C		intron	N/A	NP_055964.3
RGL1	NM_001297669.3		c.-143+11320T>C		intron	N/A	NP_001284598.1	B7Z2W5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOBEC4	ENST00000308641.6	TSL:1 MANE Select	c.961A>G	p.Asn321Asp	missense	Exon 2 of 2	ENSP00000310622.4	Q8WW27
RGL1	ENST00000304685.8	TSL:1	c.-33+11320T>C		intron	N/A	ENSP00000303192.3	Q9NZL6-2
APOBEC4	ENST00000481562.1	TSL:3	n.246-24A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1979

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0457

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00331

AC:

832

AN:

251482

AF XY:

0.00258

show subpopulations

Gnomad AFR exome

AF:

0.0469

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00134

AC:

1960

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

821

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0501

AC:

1679

AN:

33480

American (AMR)

AF:

0.00163

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1112008

Other (OTH)

AF:

0.00265

AC:

160

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

112

224

335

447

559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0130

AC:

1983

AN:

152330

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

913

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0457

AC:

1900

AN:

41568

American (AMR)

AF:

0.00418

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68042

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

190

285

380

475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00324

Hom.:

Bravo

AF:

0.0154

ESP6500AA

AF:

0.0481

AC:

212

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00414

AC:

503

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.038

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

5.4

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.10

Sift

Benign

0.10

Sift4G

Benign

0.21

Polyphen

0.99

Vest4

0.24

MVP

0.23

MPC

0.45

ClinPred

0.027

GERP RS

5.2

Varity_R

0.27

gMVP

0.11

Mutation Taster

=76/24

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over