rs868367052

Variant names:

• chr7-142942529-C-T
• rs868367052
• NM_000420.3:c.1942G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000420.3(KEL):​c.1942G>A​(p.Ala648Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000069 in 1,449,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KEL NM_000420.3 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KEL	NM_000420.3	c.1942G>A	p.Ala648Thr	missense_variant, splice_region_variant	Exon 18 of 19	ENST00000355265.7	NP_000411.1
KEL	XM_005249993.2	c.1978G>A	p.Ala660Thr	missense_variant, splice_region_variant	Exon 18 of 19		XP_005250050.1
KEL	XM_047420357.1	c.1831G>A	p.Ala611Thr	missense_variant, splice_region_variant	Exon 17 of 18		XP_047276313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KEL	ENST00000355265.7	c.1942G>A	p.Ala648Thr	missense_variant, splice_region_variant	Exon 18 of 19	1	NM_000420.3	ENSP00000347409.2
KEL	ENST00000470850.1	n.242G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	2
KEL	ENST00000478969.1	n.281G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449936 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1942G>A (p.A648T) alteration is located in exon 18 (coding exon 18) of the KEL gene. This alteration results from a G to A substitution at nucleotide position 1942, causing the alanine (A) at amino acid position 648 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.7	H
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.81		Gain of disorder (P = 0.2003);
MVP		0.95
MPC		0.38
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.040		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: rs868367052; hg19: chr7-142639616;