rs183643295

Positions:

• chr5-177404082-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000505.4(F12):​c.1027G>C​(p.Ala343Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,602,464 control chromosomes in the GnomAD database, including 37 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (32 hom.)
• Consequence: F12 NM_000505.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:8
• Conservation: PhyloP100: -0.0910

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036440194).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00145 (221/152366) while in subpopulation EAS AF= 0.028 (145/5174). AF 95% confidence interval is 0.0243. There are 5 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F12	NM_000505.4	c.1027G>C	p.Ala343Pro	missense_variant	10/14	ENST00000253496.4
F12	XM_011534462.3	c.691G>C	p.Ala231Pro	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F12	ENST00000253496.4	c.1027G>C	p.Ala343Pro	missense_variant	10/14	1	NM_000505.4	P1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152248 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00315 AC: 701 AN: 222724 Hom.: 9 AF XY: 0.00283 AC XY: 349 AN XY: 123386

Gnomad AFR exome AF: 0.0000746

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0347

Gnomad SAS exome AF: 0.000636

Gnomad FIN exome AF: 0.00489

Gnomad NFE exome AF: 0.0000406

Gnomad OTH exome AF: 0.000543

GnomAD4 exome AF: 0.00144 AC: 2093 AN: 1450098 Hom.: 32 Cov.: 33 AF XY: 0.00143 AC XY: 1030 AN XY: 721632

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0433

Gnomad4 SAS exome AF: 0.000501

Gnomad4 FIN exome AF: 0.00411

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152366 Hom.: 5 Cov.: 33 AF XY: 0.00173 AC XY: 129 AN XY: 74514

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0280

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.00130

ExAC AF: 0.00281 AC: 336

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	F12: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2021	- -

Factor XII deficiency disease Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely pathogenic, flagged submission	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2024

The p.Ala343Pro variant in F12 is classified as likely benign because it has been identified in 4.1% (1857/44756) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). ACMG/AMP Criteria applied: BS1. -

F12-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	3.2
DANN	Benign	0.87
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.20
Sift	Uncertain	0.027	D
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.70
MPC		1.1
ClinPred		0.011	T
GERP RS		-4.8
Varity_R		0.093
gMVP		0.50

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: rs183643295; hg19: chr5-176831083;