dbSNP rs8176059: KEL:p.Arg281Trp (chr7-142954267-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000420.3(KEL):c.841C>T(p.Arg281Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0093 in 1,614,062 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0068 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0096 ( 77 hom. )

Consequence

KEL
NM_000420.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0910

Publications

26 publications found

Variant links:

Genes affected

KEL (HGNC:6308): (Kell metallo-endopeptidase (Kell blood group)) This gene encodes a type II transmembrane glycoprotein that is the highly polymorphic Kell blood group antigen. The Kell glycoprotein links via a single disulfide bond to the XK membrane protein that carries the Kx antigen. The encoded protein contains sequence and structural similarity to members of the neprilysin (M13) family of zinc endopeptidases. [provided by RefSeq, Jul 2008]

KEL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042672545).

BS2

High Homozygotes in GnomAd4 at 5 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KEL	NM_000420.3 link	c.841C>T	p.Arg281Trp	missense_variant	Exon 8 of 19	ENST00000355265.7	NP_000411.1	P23276A0A077QP03
KEL	XM_005249993.2 link	c.877C>T	p.Arg293Trp	missense_variant	Exon 8 of 19		XP_005250050.1
KEL	XM_047420357.1 link	c.841C>T	p.Arg281Trp	missense_variant	Exon 8 of 18		XP_047276313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KEL	ENST00000355265.7 link	c.841C>T	p.Arg281Trp	missense_variant	Exon 8 of 19	1	NM_000420.3	ENSP00000347409.2	P23276
KEL	ENST00000479768.6 link	n.959C>T		non_coding_transcript_exon_variant	Exon 8 of 11	5
KEL	ENST00000476829.5 link	c.*77C>T		downstream_gene_variant		3		ENSP00000419889.1	E9PHG0
KEL	ENST00000494148.1 link	n.*19C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00681

AC:

1036

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00725

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00698

AC:

1752

AN:

251154

AF XY:

0.00696

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.0210

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00676

Gnomad NFE exome

AF:

0.00968

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.00956

AC:

13977

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00933

AC XY:

6784

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

33480

American (AMR)

AF:

0.00503

AC:

225

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

605

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.00220

AC:

190

AN:

86258

European-Finnish (FIN)

AF:

0.00594

AC:

317

AN:

53352

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0108

AC:

11977

AN:

1111970

Other (OTH)

AF:

0.00970

AC:

586

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

797

1595

2392

3190

3987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.00681

AC:

1037

AN:

152280

Hom.:

Cov.:

AF XY:

0.00616

AC XY:

459

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

41552

American (AMR)

AF:

0.00536

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00290

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00725

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0102

AC:

693

AN:

68016

Other (OTH)

AF:

0.0114

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

108

162

216

270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00894

Hom.:

Bravo

AF:

0.00655

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00717

AC:

871

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0100

EpiControl

AF:

0.00937

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.67

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.9

PhyloP100

0.091

PrimateAI

Benign

0.18

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.22

Sift

Uncertain

0.011

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.34

MVP

0.78

MPC

0.32

ClinPred

0.074

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.42

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over