7-142944333-T-A

Variant names:

• chr7-142944333-T-A
• rs61729032
• NM_000420.3:c.1481A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000420.3(KEL):​c.1481A>T​(p.Glu494Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000747 in 1,613,748 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (7 hom.)
• Consequence: KEL NM_000420.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.39
• Publications: 9 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 7-142944333-T-A is Benign according to our data. Variant chr7-142944333-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 3035664.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 7 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KEL	NM_000420.3	c.1481A>T	p.Glu494Val	missense_variant	Exon 13 of 19	ENST00000355265.7	NP_000411.1
KEL	XM_005249993.2	c.1517A>T	p.Glu506Val	missense_variant	Exon 13 of 19		XP_005250050.1
KEL	XM_047420357.1	c.1370A>T	p.Glu457Val	missense_variant	Exon 12 of 18		XP_047276313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KEL	ENST00000355265.7	c.1481A>T	p.Glu494Val	missense_variant	Exon 13 of 19	1	NM_000420.3	ENSP00000347409.2
KEL	ENST00000465697.1	n.342A>T		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00810

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00171 AC: 429 AN: 251478 AF XY: 0.00165

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00712

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.000360

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000702 AC: 1026 AN: 1461498 Hom.: 7 Cov.: 30 AF XY: 0.000726 AC XY: 528 AN XY: 727078

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00501 AC: 199 AN: 39694

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86250

European-Finnish (FIN) AF: 0.0125 AC: 666 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000612 AC: 68 AN: 1111660

Other (OTH) AF: 0.000927 AC: 56 AN: 60380

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74446

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00812 AC: 42 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0113 AC: 120 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000419 Hom.: 1

Bravo AF: 0.000419

ExAC AF: 0.00175 AC: 212

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KEL-related disorder Benign:1

Aug 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.33
Sift	Benign	0.17	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.79	P
Vest4		0.49
MVP		0.80
MPC		0.25
ClinPred		0.028	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.65
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 2

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

Other links and lift over

dbSNP: rs61729032; hg19: chr7-142641420; COSMIC: COSV107438483; COSMIC: COSV107438483;