1-159205720-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002036.4(ACKR1):c.281C>G(p.Pro94Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACKR1 NM_002036.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.237

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07193515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACKR1	NM_002036.4	c.281C>G	p.Pro94Arg	missense_variant	2/2	ENST00000368122.4
ACKR1	NM_001122951.3	c.287C>G	p.Pro96Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACKR1	ENST00000368122.4	c.281C>G	p.Pro94Arg	missense_variant	2/2	1	NM_002036.4	P2
ACKR1	ENST00000368121.6	c.287C>G	p.Pro96Arg	missense_variant	2/2			A2
ACKR1	ENST00000435307.2	n.462C>G		non_coding_transcript_exon_variant	1/1	3
CADM3-AS1	ENST00000609696.1	n.164+2090G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250862 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135582

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.287C>G (p.P96R) alteration is located in exon 1 (coding exon 1) of the ACKR1 gene. This alteration results from a C to G substitution at nucleotide position 287, causing the proline (P) at amino acid position 96 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	14
Dann	Benign	0.93
DEOGEN2	Benign	0.40	T;T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.056	N
LIST_S2	Uncertain	0.87	D;.;.;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.072	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.75	N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Benign	0.055
Sift	Benign	0.048	D;D;D;D
Sift4G	Uncertain	0.053	T;T;T;T
Polyphen		0.043	B;B;.;.
Vest4		0.16
MutPred		0.43		Gain of MoRF binding (P = 0.0049);Gain of MoRF binding (P = 0.0049);.;.;
MVP		0.21
MPC		0.037
ClinPred		0.079	T
GERP RS		1.9
Varity_R		0.17
gMVP		0.56

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

Other links and lift over

dbSNP: rs376764336; hg19: chr1-159175510;