5-177404825-C-G

Variant summary

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

The NM_000505.4(F12):c.619G>C(p.Ala207Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.977 in 1,607,244 control chromosomes in the GnomAD database, including 767,374 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70890 hom., cov: 31)
  • Exomes 𝑓: 0.98 (696484 hom.)
• Consequence: F12 NM_000505.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.217

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1377568E-6).
• BP6: Variant 5-177404825-C-G is Benign according to our data. Variant chr5-177404825-C-G is described in ClinVar as [Benign]. Clinvar id is 256310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177404825-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F12	NM_000505.4	c.619G>C	p.Ala207Pro	missense_variant	7/14	ENST00000253496.4
F12	XM_011534462.3	c.283G>C	p.Ala95Pro	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F12	ENST00000253496.4	c.619G>C	p.Ala207Pro	missense_variant	7/14	1	NM_000505.4	P1

Frequencies

GnomAD3 genomes AF: 0.964 AC: 146685 AN: 152086 Hom.: 70852 Cov.: 31

Gnomad AFR AF: 0.959

Gnomad AMI AF: 0.883

Gnomad AMR AF: 0.884

Gnomad ASJ AF: 0.990

Gnomad EAS AF: 0.897

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.989

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.967

GnomAD3 exomes AF: 0.949 AC: 225306 AN: 237422 Hom.: 107363 AF XY: 0.955 AC XY: 123559 AN XY: 129388

Gnomad AFR exome AF: 0.959

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.987

Gnomad EAS exome AF: 0.886

Gnomad SAS exome AF: 0.959

Gnomad FIN exome AF: 0.989

Gnomad NFE exome AF: 0.987

Gnomad OTH exome AF: 0.958

GnomAD4 exome AF: 0.978 AC: 1422839 AN: 1455040 Hom.: 696484 Cov.: 56 AF XY: 0.978 AC XY: 707450 AN XY: 723492

Gnomad4 AFR exome AF: 0.955

Gnomad4 AMR exome AF: 0.822

Gnomad4 ASJ exome AF: 0.987

Gnomad4 EAS exome AF: 0.915

Gnomad4 SAS exome AF: 0.958

Gnomad4 FIN exome AF: 0.989

Gnomad4 NFE exome AF: 0.988

Gnomad4 OTH exome AF: 0.974

GnomAD4 genome AF: 0.964 AC: 146777 AN: 152204 Hom.: 70890 Cov.: 31 AF XY: 0.962 AC XY: 71601 AN XY: 74412

Gnomad4 AFR AF: 0.959

Gnomad4 AMR AF: 0.883

Gnomad4 ASJ AF: 0.990

Gnomad4 EAS AF: 0.896

Gnomad4 SAS AF: 0.956

Gnomad4 FIN AF: 0.989

Gnomad4 NFE AF: 0.988

Gnomad4 OTH AF: 0.963

Alfa AF: 0.981 Hom.: 23697

Bravo AF: 0.954

TwinsUK AF: 0.988 AC: 3663

ALSPAC AF: 0.987 AC: 3803

ESP6500AA AF: 0.960 AC: 4218

ESP6500EA AF: 0.986 AC: 8470

ExAC AF: 0.954 AC: 115051

Asia WGS AF: 0.924 AC: 3216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

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+	-	- -

Hereditary angioedema type 3 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeMIA	-	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

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

Factor XII deficiency disease Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	9.3
Dann	Benign	0.29
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.042	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.82	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.098
Sift	Benign	0.31	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.045
MPC		0.98
ClinPred		0.014	T
GERP RS		2.1
Varity_R		0.093
gMVP		0.83

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: rs17876030; hg19: chr5-176831826; COSMIC: COSV53692430; COSMIC: COSV53692430;