rs8176038

Positions:

• chr7-142943026-A-G

Variant summary

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

The NM_000420.3(KEL):​c.1790T>C​(p.Leu597Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,614,116 control chromosomes in the GnomAD database, including 312 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (165 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (147 hom.)
• Consequence: KEL NM_000420.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: 0.569

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025378764).
• BP6: Variant 7-142943026-A-G is Benign according to our data. Variant chr7-142943026-A-G is described in ClinVar as [Benign]. Clinvar id is 31082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KEL	NM_000420.3	c.1790T>C	p.Leu597Pro	missense_variant	17/19	ENST00000355265.7	NP_000411.1
KEL	XM_005249993.2	c.1826T>C	p.Leu609Pro	missense_variant	17/19		XP_005250050.1
KEL	XM_047420357.1	c.1679T>C	p.Leu560Pro	missense_variant	16/18		XP_047276313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KEL	ENST00000355265.7	c.1790T>C	p.Leu597Pro	missense_variant	17/19	1	NM_000420.3	ENSP00000347409	P1
KEL	ENST00000478969.1	n.129T>C		non_coding_transcript_exon_variant	1/2	3
KEL	ENST00000470850.1	n.169-79T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3811 AN: 152170 Hom.: 164 Cov.: 33

Gnomad AFR AF: 0.0864

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0197

GnomAD3 exomes AF: 0.00674 AC: 1694 AN: 251394 Hom.: 67 AF XY: 0.00475 AC XY: 646 AN XY: 135898

Gnomad AFR exome AF: 0.0890

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000413

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00288 AC: 4217 AN: 1461830 Hom.: 147 Cov.: 33 AF XY: 0.00255 AC XY: 1855 AN XY: 727218

Gnomad4 AFR exome AF: 0.0923

Gnomad4 AMR exome AF: 0.00510

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.00636

GnomAD4 genome AF: 0.0251 AC: 3816 AN: 152286 Hom.: 165 Cov.: 33 AF XY: 0.0242 AC XY: 1802 AN XY: 74462

Gnomad4 AFR AF: 0.0862

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0195

Alfa AF: 0.00576 Hom.: 64

Bravo AF: 0.0288

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0869 AC: 383

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00837 AC: 1016

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -

Kel6 antigen Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 15, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.2
DANN	Benign	0.55
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	4.7	N
REVEL	Benign	0.18
Sift	Benign	0.22	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.50
MPC		0.093
ClinPred		0.00097	T
GERP RS		0.57
Varity_R		0.13
gMVP		0.40

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: rs8176038; hg19: chr7-142640113;