5-177406302-T-C

Position:

• chr5-177406302-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000505.4(F12):​c.116-241A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 151,698 control chromosomes in the GnomAD database, including 6,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (6615 hom., cov: 32)
• Consequence: F12 NM_000505.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.150

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 5-177406302-T-C is Benign according to our data. Variant chr5-177406302-T-C is described in ClinVar as [Benign]. Clinvar id is 1272279.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F12	NM_000505.4	c.116-241A>G		intron_variant		ENST00000253496.4	NP_000496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4	c.116-241A>G		intron_variant		1	NM_000505.4	ENSP00000253496.3

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43607 AN: 151580 Hom.: 6607 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.259

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.288 AC: 43639 AN: 151698 Hom.: 6615 Cov.: 32 AF XY: 0.293 AC XY: 21710 AN XY: 74140

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.263

Alfa AF: 0.162 Hom.: 312

Bravo AF: 0.278

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.72
DANN	Benign	0.43

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: rs4976648; hg19: chr5-176833303;