chr7-142942955-G-A

Position:

• chr7-142942955-G-A

Variant summary

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

The NM_000420.3(KEL):​c.1861C>T​(p.Pro621Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KEL NM_000420.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KEL	NM_000420.3	c.1861C>T	p.Pro621Ser	missense_variant	17/19	ENST00000355265.7	NP_000411.1
KEL	XM_005249993.2	c.1897C>T	p.Pro633Ser	missense_variant	17/19		XP_005250050.1
KEL	XM_047420357.1	c.1750C>T	p.Pro584Ser	missense_variant	16/18		XP_047276313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KEL	ENST00000355265.7	c.1861C>T	p.Pro621Ser	missense_variant	17/19	1	NM_000420.3	ENSP00000347409.2
KEL	ENST00000478969.1	n.200C>T		non_coding_transcript_exon_variant	1/2	3
KEL	ENST00000470850.1	n.169-8C>T		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Jun 10, 2024

The KEL c.1861C>T (p.Pro621Ser) variant was identified at a near heterozygous allelic fraction of 48.3%, a frequency which may be consistent with it being of germline origin. The KEL c.1861C>T (p.Pro621Ser) variant, to our knowledge, has not been reported in the medical literature and it is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. Computational predictors are uncertain as to the impact of this variant on KEL function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.0096
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.36
Sift	Benign	0.29	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.34
MutPred		0.58		Gain of catalytic residue at P621 (P = 0.0409);
MVP		0.82
MPC		0.28
ClinPred		0.75	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-142640042;