rs3733402

chr4-186236880-G-Achr4-186236880-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000892.5(KLKB1):c.428G>A(p.Ser143Asn) variant causes a missense change. The variant allele was found at a frequency of 0.524 in 1,613,244 control chromosomes in the GnomAD database, including 226,077 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27094 hom., cov: 30)
  • Exomes 𝑓: 0.52 (198983 hom.)
• Consequence: KLKB1 NM_000892.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 4.21

Genes affected

KLKB1 (HGNC:6371): (kallikrein B1) This gene encodes a glycoprotein that participates in the surface-dependent activation of blood coagulation, fibrinolysis, kinin generation and inflammation. The encoded preproprotein present in plasma as a non-covalent complex with high molecular weight kininogen undergoes proteolytic processing mediated by activated coagulation factor XII to generate a disulfide-linked, heterodimeric serine protease comprised of heavy and light chains. Certain mutations in this gene cause prekallikrein deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.8795765E-6).
• BP6: Variant 4-186236880-G-A is Benign according to our data. Variant chr4-186236880-G-A is described in ClinVar as [Benign]. Clinvar id is 12037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186236880-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLKB1	NM_000892.5	c.428G>A	p.Ser143Asn	missense_variant	5/15	ENST00000264690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLKB1	ENST00000264690.11	c.428G>A	p.Ser143Asn	missense_variant	5/15	1	NM_000892.5	P1

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89168 AN: 151810 Hom.: 27042 Cov.: 30

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.567

GnomAD3 exomes AF: 0.540 AC: 135782 AN: 251352 Hom.: 37996 AF XY: 0.525 AC XY: 71298 AN XY: 135838

Gnomad AFR exome AF: 0.736

Gnomad AMR exome AF: 0.629

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.671

Gnomad SAS exome AF: 0.394

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.506

Gnomad OTH exome AF: 0.537

GnomAD4 exome AF: 0.518 AC: 756256 AN: 1461314 Hom.: 198983 Cov.: 43 AF XY: 0.512 AC XY: 371965 AN XY: 726952

Gnomad4 AFR exome AF: 0.739

Gnomad4 AMR exome AF: 0.623

Gnomad4 ASJ exome AF: 0.439

Gnomad4 EAS exome AF: 0.643

Gnomad4 SAS exome AF: 0.392

Gnomad4 FIN exome AF: 0.575

Gnomad4 NFE exome AF: 0.510

Gnomad4 OTH exome AF: 0.532

GnomAD4 genome AF: 0.588 AC: 89276 AN: 151930 Hom.: 27094 Cov.: 30 AF XY: 0.587 AC XY: 43554 AN XY: 74240

Gnomad4 AFR AF: 0.738

Gnomad4 AMR AF: 0.585

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.680

Gnomad4 SAS AF: 0.401

Gnomad4 FIN AF: 0.582

Gnomad4 NFE AF: 0.511

Gnomad4 OTH AF: 0.568

Alfa AF: 0.522 Hom.: 36509

Bravo AF: 0.599

TwinsUK AF: 0.526 AC: 1950

ALSPAC AF: 0.502 AC: 1933

ESP6500AA AF: 0.736 AC: 3245

ESP6500EA AF: 0.507 AC: 4357

ExAC AF: 0.536 AC: 65105

Asia WGS AF: 0.532 AC: 1851 AN: 3478

EpiCase AF: 0.499

EpiControl AF: 0.499

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.729, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Prekallikrein deficiency Pathogenic:1 Benign:1

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000892.3:c.428G>A (Ser143Asn) in the KLKB1 gene has an allele frequency of 0.738 in African subpopulation in the gnomAD database, including 43762 homozygous events. Ser143Asn was reported as N124S according to ClinVar's annotation. Katsuda et al reported three Japanese patients with plasma prekallikrein deficiency, who harbors homozygousity of Gly104Arg and Asn124Ser in 2007. Co-segregate analysis demonstrate the proband's parents were heterozygous of Gly104Arg Asn124-Ser\Gly104Arg+ (PMID: 17598838). Considering the high frequency of this variant, we classify the variant as benign. ACMG/AMP criteria applied: BA1, BS2. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 20981092, 24625756, 23251661, 17598838, 28508493, 28492530) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	7.3
Dann	Benign	0.17
DEOGEN2	Benign	0.21	T;.;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.081	T;.;T;T
MetaRNN	Benign	0.0000039	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.4	N;N;N;.
REVEL	Benign	0.22
Sift	Benign	1.0	T;T;T;.
Sift4G	Benign	1.0	T;T;T;T
Vest4		0.22, 0.21
MPC		0.10
ClinPred		0.0033	T
GERP RS		4.9
gMVP		0.081

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: rs3733402; hg19: chr4-187158034; COSMIC: COSV52993977;