NM_002036.4:c.265C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_002036.4(ACKR1):c.265C>T(p.Arg89Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,216 control chromosomes in the GnomAD database, including 197 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0099 ( 13 hom., cov: 33)

Exomes 𝑓: 0.013 ( 184 hom. )

Consequence

ACKR1
NM_002036.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1B:2

Conservation

PhyloP100: 0.887

Publications

57 publications found

Variant links:

Genes affected

ACKR1 (HGNC:4035): (atypical chemokine receptor 1 (Duffy blood group)) The protein encoded by this gene is a glycosylated membrane protein and a non-specific receptor for several chemokines. The encoded protein is the receptor for the human malarial parasites Plasmodium vivax and Plasmodium knowlesi. Polymorphisms in this gene are the basis of the Duffy blood group system. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACKR1 links:

CADM3-AS1 (HGNC:40812): (CADM3 antisense RNA 1)

CADM3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026265323).

BP6

Variant 1-159205704-C-T is Benign according to our data. Variant chr1-159205704-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 18396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00992 (1511/152340) while in subpopulation NFE AF = 0.0163 (1106/68032). AF 95% confidence interval is 0.0155. There are 13 homozygotes in GnomAd4. There are 696 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 BG geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002036.4. 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
	ACKR1	NM_002036.4	MANE Select	c.265C>T	p.Arg89Cys	missense	Exon 2 of 2	NP_002027.2
	ACKR1	NM_001122951.3		c.271C>T	p.Arg91Cys	missense	Exon 2 of 2	NP_001116423.1	Q16570-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACKR1	ENST00000368122.4	TSL:1 MANE Select	c.265C>T	p.Arg89Cys	missense	Exon 2 of 2	ENSP00000357104.1	Q16570-1
ACKR1	ENST00000368121.6	TSL:6	c.271C>T	p.Arg91Cys	missense	Exon 2 of 2	ENSP00000357103.2	Q16570-2
ACKR1	ENST00000851528.1		c.265C>T	p.Arg89Cys	missense	Exon 3 of 3	ENSP00000521587.1

Frequencies

GnomAD3 genomes

AF:

0.00993

AC:

1512

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00909

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.0112

AC:

2818

AN:

250772

AF XY:

0.0121

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00914

Gnomad ASJ exome

AF:

0.0138

Gnomad EAS exome

AF:

0.00120

Gnomad FIN exome

AF:

0.00481

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.0128

AC:

18703

AN:

1461876

Hom.:

184

Cov.:

AF XY:

0.0130

AC XY:

9463

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

33480

American (AMR)

AF:

0.00921

AC:

412

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

304

AN:

26136

East Asian (EAS)

AF:

0.000705

AC:

AN:

39700

South Asian (SAS)

AF:

0.0117

AC:

1008

AN:

86256

European-Finnish (FIN)

AF:

0.00517

AC:

276

AN:

53406

Middle Eastern (MID)

AF:

0.0163

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0141

AC:

15703

AN:

1112012

Other (OTH)

AF:

0.0134

AC:

810

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1232

2463

3695

4926

6158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

554

1108

1662

2216

2770

<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:

0.00992

AC:

1511

AN:

152340

Hom.:

Cov.:

AF XY:

0.00934

AC XY:

696

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41584

American (AMR)

AF:

0.00908

AC:

139

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5172

South Asian (SAS)

AF:

0.00953

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00386

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0163

AC:

1106

AN:

68032

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0134

Hom.:

Bravo

AF:

0.00958

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0156

AC:

134

ExAC

AF:

0.0107

AC:

1301

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0182

EpiControl

AF:

0.0197

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

ACKR1-related disorder (1)

DUFFY BLOOD GROUP SYSTEM, FY(bwk) PHENOTYPE (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.70

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

0.89

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.3

REVEL

Benign

0.10

Sift

Benign

0.11

Sift4G

Benign

0.14

Polyphen

0.99

Vest4

0.062

MPC

0.14

ClinPred

0.0093

GERP RS

3.0

Varity_R

0.094

gMVP

0.32

Mutation Taster

=93/7

disease causing (ClinVar)

(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