rs17876031

Positions:

• chr5-177404118-A-G
• chr5-177404118-A-T

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.1019-28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,593,896 control chromosomes in the GnomAD database, including 306,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24672 hom., cov: 34)
  • Exomes 𝑓: 0.62 (281943 hom.)
• Consequence: F12 NM_000505.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01

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]

F12 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-177404118-A-G is Benign according to our data. Variant chr5-177404118-A-G is described in ClinVar as [Benign]. Clinvar id is 1181607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F12	NM_000505.4	c.1019-28T>C		intron_variant		ENST00000253496.4	NP_000496.2
F12	XM_011534462.3	c.683-28T>C		intron_variant			XP_011532764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4	c.1019-28T>C		intron_variant		1	NM_000505.4	ENSP00000253496.3

Frequencies

GnomAD3 genomes AF: 0.553 AC: 84047 AN: 152022 Hom.: 24672 Cov.: 34

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.595

GnomAD3 exomes AF: 0.543 AC: 111107 AN: 204612 Hom.: 32496 AF XY: 0.554 AC XY: 62655 AN XY: 113144

Gnomad AFR exome AF: 0.408

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.230

Gnomad SAS exome AF: 0.447

Gnomad FIN exome AF: 0.677

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.596

GnomAD4 exome AF: 0.617 AC: 889922 AN: 1441756 Hom.: 281943 Cov.: 81 AF XY: 0.614 AC XY: 439852 AN XY: 716276

Gnomad4 AFR exome AF: 0.390

Gnomad4 AMR exome AF: 0.402

Gnomad4 ASJ exome AF: 0.714

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.451

Gnomad4 FIN exome AF: 0.676

Gnomad4 NFE exome AF: 0.654

Gnomad4 OTH exome AF: 0.594

GnomAD4 genome AF: 0.552 AC: 84057 AN: 152140 Hom.: 24672 Cov.: 34 AF XY: 0.550 AC XY: 40926 AN XY: 74388

Gnomad4 AFR AF: 0.403

Gnomad4 AMR AF: 0.522

Gnomad4 ASJ AF: 0.714

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.690

Gnomad4 NFE AF: 0.652

Gnomad4 OTH AF: 0.592

Alfa AF: 0.638 Hom.: 14173

Bravo AF: 0.534

Asia WGS AF: 0.355 AC: 1237 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary angioedema type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.6
DANN	Benign	0.42

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: rs17876031; hg19: chr5-176831119;