chr5-177403740-G-A

Position:

• chr5-177403740-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000505.4(F12):​c.1250+119C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00639 in 1,480,942 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (34 hom.)
• Consequence: F12 NM_000505.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.09

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• 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.1250+119C>T		intron_variant		ENST00000253496.4
F12	XM_011534462.3	c.914+119C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F12	ENST00000253496.4	c.1250+119C>T		intron_variant		1	NM_000505.4	P1

Frequencies

GnomAD3 genomes AF: 0.00552 AC: 840 AN: 152224 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00634

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00763

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00649 AC: 8623 AN: 1328600 Hom.: 34 Cov.: 29 AF XY: 0.00641 AC XY: 4172 AN XY: 650624

Gnomad4 AFR exome AF: 0.000683

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.0000281

Gnomad4 SAS exome AF: 0.00281

Gnomad4 FIN exome AF: 0.00622

Gnomad4 NFE exome AF: 0.00710

Gnomad4 OTH exome AF: 0.00632

GnomAD4 genome AF: 0.00551 AC: 839 AN: 152342 Hom.: 5 Cov.: 33 AF XY: 0.00558 AC XY: 416 AN XY: 74492

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00633

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00819

Gnomad4 NFE AF: 0.00763

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00551 Hom.: 0

Bravo AF: 0.00534

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41309760; hg19: chr5-176830741;