4-186258332-A-G

Variant names:

• chr4-186258332-A-G
• rs3087505
• NM_000892.5:c.*120A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000892.5(KLKB1):​c.*120A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.897 in 903,306 control chromosomes in the GnomAD database, including 363,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (62621 hom., cov: 33)
  • Exomes 𝑓: 0.90 (301101 hom.)
• Consequence: KLKB1 NM_000892.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.78
• Publications: 23 publications found

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]

KLKB1 Gene-Disease associations (from GenCC):

• inherited prekallikrein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000290316 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-186258332-A-G is Benign according to our data. Variant chr4-186258332-A-G is described in ClinVar as Benign. ClinVar VariationId is 1278744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.*120A>G		3_prime_UTR_variant	Exon 15 of 15	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11	c.*120A>G		3_prime_UTR_variant	Exon 15 of 15	1	NM_000892.5	ENSP00000264690.6
ENSG00000290316	ENST00000511608.5	c.*120A>G		3_prime_UTR_variant	Exon 15 of 15	5		ENSP00000426629.1

Frequencies

GnomAD3 genomes AF: 0.907 AC: 137945 AN: 152158 Hom.: 62566 Cov.: 33

Gnomad AFR AF: 0.932

Gnomad AMI AF: 0.988

Gnomad AMR AF: 0.893

Gnomad ASJ AF: 0.900

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.890

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.894

Gnomad OTH AF: 0.920

GnomAD4 exome AF: 0.895 AC: 672321 AN: 751030 Hom.: 301101 Cov.: 10 AF XY: 0.894 AC XY: 352175 AN XY: 393934

African (AFR) AF: 0.930 AC: 17834 AN: 19174

American (AMR) AF: 0.882 AC: 30778 AN: 34878

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 18998 AN: 21098

East Asian (EAS) AF: 0.940 AC: 30830 AN: 32814

South Asian (SAS) AF: 0.879 AC: 57641 AN: 65582

European-Finnish (FIN) AF: 0.898 AC: 42662 AN: 47508

Middle Eastern (MID) AF: 0.907 AC: 2541 AN: 2800

European-Non Finnish (NFE) AF: 0.893 AC: 438000 AN: 490518

Other (OTH) AF: 0.901 AC: 33037 AN: 36658

GnomAD4 genome AF: 0.907 AC: 138056 AN: 152276 Hom.: 62621 Cov.: 33 AF XY: 0.906 AC XY: 67484 AN XY: 74448

African (AFR) AF: 0.932 AC: 38714 AN: 41544

American (AMR) AF: 0.893 AC: 13664 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 3124 AN: 3472

East Asian (EAS) AF: 0.934 AC: 4832 AN: 5176

South Asian (SAS) AF: 0.889 AC: 4286 AN: 4822

European-Finnish (FIN) AF: 0.893 AC: 9476 AN: 10606

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.894 AC: 60841 AN: 68028

Other (OTH) AF: 0.920 AC: 1947 AN: 2116

Alfa AF: 0.898 Hom.: 96942

Bravo AF: 0.907

Asia WGS AF: 0.910 AC: 3164 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

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.25
DANN	Benign	0.40
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3087505; hg19: chr4-187179486;