rs4253301

Positions:

• chr4-186251858-T-A
• chr4-186251858-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000892.5(KLKB1):​c.1141T>A​(p.Ser381Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S381A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KLKB1 NM_000892.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.318

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08109999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLKB1	NM_000892.5	c.1141T>A	p.Ser381Thr	missense_variant	10/15	ENST00000264690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLKB1	ENST00000264690.11	c.1141T>A	p.Ser381Thr	missense_variant	10/15	1	NM_000892.5	P1
KLKB1	ENST00000511406.5	n.1202T>A		non_coding_transcript_exon_variant	10/15	1
KLKB1	ENST00000513864.2	c.1027T>A	p.Ser343Thr	missense_variant	11/15	2
KLKB1	ENST00000467271.1	n.570T>A		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250684 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458604 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725870

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	11
DANN	Benign	0.82
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.57	N;.
REVEL	Benign	0.20
Sift	Benign	0.14	T;.
Sift4G	Benign	0.32	T;T
Vest4		0.062
MutPred		0.29		Loss of ubiquitination at K386 (P = 0.0935);.;
MVP		0.54
MPC		0.30
ClinPred		0.059	T
GERP RS		-2.6
gMVP		0.45

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: rs4253301; hg19: chr4-187173012;