rs8176059

Positions:

• chr7-142954267-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R281Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (77 hom.)
• Consequence: KEL NM_000420.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0910

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
KEL	NM_000420.3	c.841C>T	p.Arg281Trp	missense_variant	8/19	ENST00000355265.7	NP_000411.1
KEL	XM_005249993.2	c.877C>T	p.Arg293Trp	missense_variant	8/19		XP_005250050.1
KEL	XM_047420357.1	c.841C>T	p.Arg281Trp	missense_variant	8/18		XP_047276313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KEL	ENST00000355265.7	c.841C>T	p.Arg281Trp	missense_variant	8/19	1	NM_000420.3	ENSP00000347409	P1
KEL	ENST00000479768.6	n.959C>T		non_coding_transcript_exon_variant	8/11	5
KEL	ENST00000494148.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00681 AC: 1036 AN: 152162 Hom.: 5 Cov.: 32

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

GnomAD3 exomes AF: 0.00698 AC: 1752 AN: 251154 Hom.: 10 AF XY: 0.00696 AC XY: 945 AN XY: 135712

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 SAS exome AF: 0.00157

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.: 77 Cov.: 33 AF XY: 0.00933 AC XY: 6784 AN XY: 727192

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.0231

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00220

Gnomad4 FIN exome AF: 0.00594

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00970

GnomAD4 genome AF: 0.00681 AC: 1037 AN: 152280 Hom.: 5 Cov.: 32 AF XY: 0.00616 AC XY: 459 AN XY: 74480

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00725

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00953 Hom.: 11

Bravo AF: 0.00655

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00717 AC: 871

Asia WGS AF: 0.00144 AC: 6 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	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.18	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.22
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.34
MVP		0.78
MPC		0.32
ClinPred		0.074	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs8176059; hg19: chr7-142651354;