rs17876032

chr5-177403626-G-Achr5-177403626-G-Cchr5-177403626-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000505.4(F12):c.1251-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,600,484 control chromosomes in the GnomAD database, including 296,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 21090 hom., cov: 33)

Exomes 𝑓: 0.60 ( 275054 hom. )

Consequence

F12
NM_000505.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001529

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.732

Variant links:

Genes affected

F12 (HGNC:3530): (coagulation factor XII) This gene encodes coagulation factor XII which circulates in blood as a zymogen. This single chain zymogen is converted to a two-chain serine protease with an heavy chain (alpha-factor XIIa) and a light chain. The heavy chain contains two fibronectin-type domains, two epidermal growth factor (EGF)-like domains, a kringle domain and a proline-rich domain, whereas the light chain contains only a catalytic domain. On activation, further cleavages takes place in the heavy chain, resulting in the production of beta-factor XIIa light chain and the alpha-factor XIIa light chain becomes beta-factor XIIa heavy chain. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then to beta-factor XIIa. The active factor XIIa participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. It activates coagulation factors VII and XI. Defects in this gene do not cause any clinical symptoms and the sole effect is that whole-blood clotting time is prolonged. [provided by RefSeq, Jul 2008]

F12 links:

GRK6 (HGNC:4545): (G protein-coupled receptor kinase 6) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates the activated forms of G protein-coupled receptors thus initiating their deactivation. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

GRK6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 5-177403626-G-A is Benign according to our data. Variant chr5-177403626-G-A is described in ClinVar as [Benign]. Clinvar id is 256309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177403626-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F12	NM_000505.4 linkuse as main transcript	c.1251-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000253496.4
F12	XM_011534462.3 linkuse as main transcript	c.915-9C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F12	ENST00000253496.4 linkuse as main transcript	c.1251-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000505.4	P1

Frequencies

GnomAD3 genomes

AF:

0.472

AC:

71788

AN:

152016

Hom.:

21097

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.650

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.676

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.382

Gnomad FIN

AF:

0.690

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.647

Gnomad OTH

AF:

0.529

GnomAD3 exomes

AF:

0.517

AC:

120945

AN:

233808

Hom.:

35388

AF XY:

0.531

AC XY:

68533

AN XY:

129002

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.365

Gnomad ASJ exome

AF:

0.678

Gnomad EAS exome

AF:

0.225

Gnomad SAS exome

AF:

0.401

Gnomad FIN exome

AF:

0.687

Gnomad NFE exome

AF:

0.656

Gnomad OTH exome

AF:

0.578

GnomAD4 exome

AF:

0.603

AC:

873388

AN:

1448350

Hom.:

275054

Cov.:

AF XY:

0.600

AC XY:

432178

AN XY:

720510

show subpopulations

Gnomad4 AFR exome

AF:

0.117

Gnomad4 AMR exome

AF:

0.382

Gnomad4 ASJ exome

AF:

0.677

Gnomad4 EAS exome

AF:

0.269

Gnomad4 SAS exome

AF:

0.409

Gnomad4 FIN exome

AF:

0.679

Gnomad4 NFE exome

AF:

0.650

Gnomad4 OTH exome

AF:

0.569

GnomAD4 genome

AF:

0.472

AC:

71781

AN:

152134

Hom.:

21090

Cov.:

AF XY:

0.472

AC XY:

35084

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.138

Gnomad4 AMR

AF:

0.493

Gnomad4 ASJ

AF:

0.676

Gnomad4 EAS

AF:

0.224

Gnomad4 SAS

AF:

0.384

Gnomad4 FIN

AF:

0.690

Gnomad4 NFE

AF:

0.647

Gnomad4 OTH

AF:

0.527

Alfa

AF:

0.615

Hom.:

35918

Bravo

AF:

0.444

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Hereditary angioedema type 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary angioneurotic edema

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Factor XII deficiency disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Nephrolithiasis/osteoporosis, hypophosphatemic

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

Cadd

Benign

8.2

Dann

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000015

dbscSNV1_RF

Benign

0.0040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over