rs8176039

Variant names:

• chr7-142942917-T-C
• rs8176039
• NM_000420.3:c.1899A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000420.3(KEL):​c.1899A>G​(p.Leu633Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,064 control chromosomes in the GnomAD database, including 1,890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.062 (969 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (921 hom.)
• Consequence: KEL NM_000420.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.380
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-142942917-T-C is Benign according to our data. Variant chr7-142942917-T-C is described in ClinVar as [Benign]. Clinvar id is 3056220.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KEL	NM_000420.3	c.1899A>G	p.Leu633Leu	synonymous_variant	Exon 17 of 19	ENST00000355265.7	NP_000411.1
KEL	XM_005249993.2	c.1935A>G	p.Leu645Leu	synonymous_variant	Exon 17 of 19		XP_005250050.1
KEL	XM_047420357.1	c.1788A>G	p.Leu596Leu	synonymous_variant	Exon 16 of 18		XP_047276313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KEL	ENST00000355265.7	c.1899A>G	p.Leu633Leu	synonymous_variant	Exon 17 of 19	1	NM_000420.3	ENSP00000347409.2
KEL	ENST00000470850.1	n.199A>G		non_coding_transcript_exon_variant	Exon 3 of 4	2
KEL	ENST00000478969.1	n.238A>G		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0618 AC: 9400 AN: 152064 Hom.: 969 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0246

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.0469

GnomAD2 exomes AF: 0.0174 AC: 4362 AN: 251392 AF XY: 0.0122

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00714 AC: 10442 AN: 1461882 Hom.: 921 Cov.: 33 AF XY: 0.00621 AC XY: 4513 AN XY: 727248

African (AFR) AF: 0.227 AC: 7604 AN: 33476

American (AMR) AF: 0.0151 AC: 677 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.0208 AC: 120 AN: 5768

European-Non Finnish (NFE) AF: 0.000947 AC: 1053 AN: 1112012

Other (OTH) AF: 0.0149 AC: 899 AN: 60392

GnomAD4 genome AF: 0.0619 AC: 9414 AN: 152182 Hom.: 969 Cov.: 33 AF XY: 0.0582 AC XY: 4329 AN XY: 74396

African (AFR) AF: 0.213 AC: 8833 AN: 41486

American (AMR) AF: 0.0246 AC: 376 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 68004

Other (OTH) AF: 0.0464 AC: 98 AN: 2112

Alfa AF: 0.0496 Hom.: 802

Bravo AF: 0.0710

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KEL-related disorder Benign:1

Dec 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.0
DANN	Benign	0.50
PhyloP100		0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8176039; hg19: chr7-142640004; COSMIC: COSV62336775; COSMIC: COSV62336775;