chr5-177409531-A-G

Variant names:

Variant summary

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

The NM_000505.4(F12):c.-4T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,613,300 control chromosomes in the GnomAD database, including 413,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 34772 hom., cov: 31)

Exomes 𝑓: 0.71 ( 378507 hom. )

Consequence

F12
NM_000505.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.57

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 5-177409531-A-G is Benign according to our data. Variant chr5-177409531-A-G is described in ClinVar as [Benign]. Clinvar id is 1167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177409531-A-G is described in Lovd as [Benign]. Variant chr5-177409531-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F12	NM_000505.4 link	c.-4T>C		5_prime_UTR_variant	Exon 1 of 14	ENST00000253496.4	NP_000496.2	P00748Q8IZZ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4 link	c.-4T>C		5_prime_UTR_variant	Exon 1 of 14	1	NM_000505.4	ENSP00000253496.3		P00748

Frequencies

GnomAD3 genomes

AF:

0.665

AC:

100982

AN:

151938

Hom.:

34763

Cov.:

show subpopulations

Gnomad AFR

AF:

0.552

Gnomad AMI

AF:

0.874

Gnomad AMR

AF:

0.665

Gnomad ASJ

AF:

0.816

Gnomad EAS

AF:

0.254

Gnomad SAS

AF:

0.519

Gnomad FIN

AF:

0.740

Gnomad MID

AF:

0.788

Gnomad NFE

AF:

0.751

Gnomad OTH

AF:

0.705

GnomAD3 exomes

AF:

0.652

AC:

163419

AN:

250654

Hom.:

56358

AF XY:

0.659

AC XY:

89311

AN XY:

135526

show subpopulations

Gnomad AFR exome

AF:

0.553

Gnomad AMR exome

AF:

0.562

Gnomad ASJ exome

AF:

0.808

Gnomad EAS exome

AF:

0.242

Gnomad SAS exome

AF:

0.547

Gnomad FIN exome

AF:

0.733

Gnomad NFE exome

AF:

0.757

Gnomad OTH exome

AF:

0.702

GnomAD4 exome

AF:

0.713

AC:

1041628

AN:

1461244

Hom.:

378507

Cov.:

AF XY:

0.710

AC XY:

516241

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.543

Gnomad4 AMR exome

AF:

0.578

Gnomad4 ASJ exome

AF:

0.811

Gnomad4 EAS exome

AF:

0.303

Gnomad4 SAS exome

AF:

0.556

Gnomad4 FIN exome

AF:

0.734

Gnomad4 NFE exome

AF:

0.748

Gnomad4 OTH exome

AF:

0.691

GnomAD4 genome

AF:

0.664

AC:

101032

AN:

152056

Hom.:

34772

Cov.:

AF XY:

0.660

AC XY:

49035

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.552

Gnomad4 AMR

AF:

0.664

Gnomad4 ASJ

AF:

0.816

Gnomad4 EAS

AF:

0.254

Gnomad4 SAS

AF:

0.519

Gnomad4 FIN

AF:

0.740

Gnomad4 NFE

AF:

0.751

Gnomad4 OTH

AF:

0.700

Alfa

AF:

0.737

Hom.:

81958

Bravo

AF:

0.657

Asia WGS

AF:

0.415

AC:

1448

AN:

3478

EpiCase

AF:

0.764

EpiControl

AF:

0.774

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Hereditary angioedema type 3

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CeMIA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (BA1), allele frequency is greater than expected for disorder (BS1), it is observed in a healthy adult individual (BS2), it is predicted to be benign by multiple in silico algorithms (BP4), it is found in a case with an alternate molecular basis for the disease (BP5) and/or reputable source recently reports variant as benign (BP6). -

not provided

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21071604, 20814302, 9490684, 16170239, 19933701, 18180442, 19372376, 19786295, 16411408, 29513108, 26248961) -

Factor XII deficiency disease

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

F12 POLYMORPHISM

Benign:1

Apr 09, 2010

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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