rs12075

chr1-159205564-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002036.4(ACKR1):c.125G>A(p.Gly42Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,613,990 control chromosomes in the GnomAD database, including 269,798 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.64 (34587 hom., cov: 33)
  • Exomes 𝑓: 0.56 (235211 hom.)
• Consequence: ACKR1 NM_002036.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.192

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]

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.9943995E-7).
• BP6: Variant 1-159205564-G-A is Benign according to our data. Variant chr1-159205564-G-A is described in ClinVar as [Benign]. Clinvar id is 17728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACKR1	NM_002036.4	c.125G>A	p.Gly42Asp	missense_variant	2/2	ENST00000368122.4
ACKR1	NM_001122951.3	c.131G>A	p.Gly44Asp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACKR1	ENST00000368122.4	c.125G>A	p.Gly42Asp	missense_variant	2/2	1	NM_002036.4	P2
ACKR1	ENST00000368121.6	c.131G>A	p.Gly44Asp	missense_variant	2/2			A2
ACKR1	ENST00000435307.2	n.306G>A		non_coding_transcript_exon_variant	1/1	3
CADM3-AS1	ENST00000609696.1	n.164+2246C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97626 AN: 152086 Hom.: 34532 Cov.: 33

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.0638

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.659

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.634

GnomAD3 exomes AF: 0.512 AC: 128658 AN: 251268 Hom.: 37310 AF XY: 0.506 AC XY: 68752 AN XY: 135808

Gnomad AFR exome AF: 0.933

Gnomad AMR exome AF: 0.434

Gnomad ASJ exome AF: 0.552

Gnomad EAS exome AF: 0.0498

Gnomad SAS exome AF: 0.383

Gnomad FIN exome AF: 0.511

Gnomad NFE exome AF: 0.579

Gnomad OTH exome AF: 0.560

GnomAD4 exome AF: 0.555 AC: 811380 AN: 1461786 Hom.: 235211 Cov.: 66 AF XY: 0.548 AC XY: 398869 AN XY: 727200

Gnomad4 AFR exome AF: 0.939

Gnomad4 AMR exome AF: 0.448

Gnomad4 ASJ exome AF: 0.553

Gnomad4 EAS exome AF: 0.0785

Gnomad4 SAS exome AF: 0.384

Gnomad4 FIN exome AF: 0.518

Gnomad4 NFE exome AF: 0.579

Gnomad4 OTH exome AF: 0.563

GnomAD4 genome AF: 0.642 AC: 97720 AN: 152204 Hom.: 34587 Cov.: 33 AF XY: 0.629 AC XY: 46835 AN XY: 74408

Gnomad4 AFR AF: 0.923

Gnomad4 AMR AF: 0.566

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.0634

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.499

Gnomad4 NFE AF: 0.579

Gnomad4 OTH AF: 0.628

Alfa AF: 0.579 Hom.: 65875

Bravo AF: 0.657

TwinsUK AF: 0.576 AC: 2137

ALSPAC AF: 0.571 AC: 2199

ESP6500AA AF: 0.916 AC: 4037

ESP6500EA AF: 0.578 AC: 4967

ExAC AF: 0.523 AC: 63517

Asia WGS AF: 0.275 AC: 962 AN: 3478

EpiCase AF: 0.580

EpiControl AF: 0.591

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 27, 2016

p.Gly42Asp in exon 2 of DARC: This variant is not expected to have clinical sign ificance because it has been identified in 92.68% (9644/10406) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs12075). -

ACKR1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

DUFFY BLOOD GROUP SYSTEM, FYA/FYB POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Aug 10, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.68
Dann	Benign	0.48
DEOGEN2	Benign	0.060	T;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.45	T;.;.;T
MetaRNN	Benign	9.0e-7	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.4	N;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.5	N;N;N;N
REVEL	Benign	0.036
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.91	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.019
MPC		0.030
ClinPred		0.0062	T
GERP RS		-1.1
Varity_R		0.035
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs12075; hg19: chr1-159175354; COSMIC: COSV63672326; COSMIC: COSV63672326;