7-142943829-G-T

Variant names:

• chr7-142943829-G-T
• rs8176034
• NM_000420.3:c.1546C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000420.3(KEL):​c.1546C>A​(p.Arg516Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,614,170 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (35 hom.)
• Consequence: KEL NM_000420.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.21
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-142943829-G-T is Benign according to our data. Variant chr7-142943829-G-T is described in ClinVar as Benign. ClinVar VariationId is 784500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1538/152286) while in subpopulation AFR AF = 0.0282 (1171/41556). AF 95% confidence interval is 0.0268. There are 12 homozygotes in GnomAd4. There are 758 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 BG gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000420.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KEL	NM_000420.3	MANE Select	c.1546C>A	p.Arg516Arg	synonymous	Exon 14 of 19	NP_000411.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KEL	ENST00000355265.7	TSL:1 MANE Select	c.1546C>A	p.Arg516Arg	synonymous	Exon 14 of 19	ENSP00000347409.2
	KEL	ENST00000465697.1	TSL:3	n.407C>A		non_coding_transcript_exon	Exon 3 of 4
	KEL	ENST00000470850.1	TSL:2	n.11C>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1534 AN: 152168 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00480 AC: 1206 AN: 251300 AF XY: 0.00434

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00285 AC: 4163 AN: 1461884 Hom.: 35 Cov.: 33 AF XY: 0.00281 AC XY: 2043 AN XY: 727240

African (AFR) AF: 0.0298 AC: 997 AN: 33480

American (AMR) AF: 0.00608 AC: 272 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 691 AN: 26136

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

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86256

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53420

Middle Eastern (MID) AF: 0.0114 AC: 66 AN: 5768

European-Non Finnish (NFE) AF: 0.00153 AC: 1700 AN: 1112006

Other (OTH) AF: 0.00672 AC: 406 AN: 60396

GnomAD4 genome AF: 0.0101 AC: 1538 AN: 152286 Hom.: 12 Cov.: 32 AF XY: 0.0102 AC XY: 758 AN XY: 74470

African (AFR) AF: 0.0282 AC: 1171 AN: 41556

American (AMR) AF: 0.00915 AC: 140 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68018

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0100 Hom.: 12

Bravo AF: 0.0114

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.9
DANN	Benign	0.82
PhyloP100		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs8176034; hg19: chr7-142640916;