5-177403621-C-CG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000505.4(F12):c.1251-5_1251-4insC variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000414 in 1,599,220 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: F12 NM_000505.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.919

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 -8 ACMG points.

• BP6: Variant 5-177403621-C-CG is Benign according to our data. Variant chr5-177403621-C-CG is described in ClinVar as [Likely_benign]. Clinvar id is 1879642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F12	NM_000505.4	c.1251-5_1251-4insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000253496.4
F12	XM_011534462.3	c.915-5_915-4insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F12	ENST00000253496.4	c.1251-5_1251-4insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000505.4	P1

Frequencies

GnomAD3 genomes AF: 0.000968 AC: 147 AN: 151820 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000584 AC: 132 AN: 226026 Hom.: 1 AF XY: 0.000624 AC XY: 78 AN XY: 124984

Gnomad AFR exome AF: 0.00248

Gnomad AMR exome AF: 0.000489

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000181

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.000203

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.000529

GnomAD4 exome AF: 0.000355 AC: 514 AN: 1447288 Hom.: 2 Cov.: 31 AF XY: 0.000410 AC XY: 295 AN XY: 719848

Gnomad4 AFR exome AF: 0.00380

Gnomad4 AMR exome AF: 0.000428

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.000109

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.000702

GnomAD4 genome AF: 0.000974 AC: 148 AN: 151932 Hom.: 0 Cov.: 33 AF XY: 0.000875 AC XY: 65 AN XY: 74256

Gnomad4 AFR AF: 0.00276

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00190

Bravo AF: 0.00116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	F12: BP4 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 09, 2023	- -

F12-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as likely 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

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: rs530070405; hg19: chr5-176830622;