rs8176058

Positions:

• chr7-142957921-G-A
• chr7-142957921-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000420.3(KEL):​c.578C>T​(p.Thr193Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,614,034 control chromosomes in the GnomAD database, including 1,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.026 (70 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1116 hom.)
• Consequence: KEL NM_000420.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.00

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013251543).
• BP6: Variant 7-142957921-G-A is Benign according to our data. Variant chr7-142957921-G-A is described in ClinVar as [Benign]. Clinvar id is 17722.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-142957921-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0261 (3968/152230) while in subpopulation NFE AF= 0.0414 (2818/68010). AF 95% confidence interval is 0.0402. There are 70 homozygotes in gnomad4. There are 1791 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 70 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KEL	NM_000420.3	c.578C>T	p.Thr193Met	missense_variant	6/19	ENST00000355265.7	NP_000411.1
KEL	XM_005249993.2	c.614C>T	p.Thr205Met	missense_variant	6/19		XP_005250050.1
KEL	XM_047420357.1	c.578C>T	p.Thr193Met	missense_variant	6/18		XP_047276313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KEL	ENST00000355265.7	c.578C>T	p.Thr193Met	missense_variant	6/19	1	NM_000420.3	ENSP00000347409	P1

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3972 AN: 152112 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00886

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0567

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00953

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0269 AC: 6762 AN: 251390 Hom.: 143 AF XY: 0.0278 AC XY: 3774 AN XY: 135862

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0121

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0332

GnomAD4 exome AF: 0.0366 AC: 53573 AN: 1461804 Hom.: 1116 Cov.: 33 AF XY: 0.0362 AC XY: 26330 AN XY: 727214

Gnomad4 AFR exome AF: 0.00815

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.0602

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0131

Gnomad4 FIN exome AF: 0.0195

Gnomad4 NFE exome AF: 0.0418

Gnomad4 OTH exome AF: 0.0353

GnomAD4 genome AF: 0.0261 AC: 3968 AN: 152230 Hom.: 70 Cov.: 32 AF XY: 0.0241 AC XY: 1791 AN XY: 74432

Gnomad4 AFR AF: 0.00881

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.0567

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00954

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.0414

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0397 Hom.: 219

Bravo AF: 0.0264

TwinsUK AF: 0.0515 AC: 191

ALSPAC AF: 0.0402 AC: 155

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.0414 AC: 356

ExAC AF: 0.0274 AC: 3325

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0408

EpiControl AF: 0.0413

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

KELL K/k BLOOD GROUP POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jun 01, 1996

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.079
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.22
Sift	Benign	0.039	D
Sift4G	Uncertain	0.049	D
Polyphen		0.96	D
Vest4		0.085
MPC		0.39
ClinPred		0.028	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs8176058; hg19: chr7-142655008; COSMIC: COSV62334933; COSMIC: COSV62334933;