rs41309744

Positions:

• chr5-177406332-CA-C
• chr5-177406332-CA-CAA
• chr5-177406332-CA-CAAAAAA
• chr5-177406332-CA-CAAAAAAA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000253496.4(F12):​c.116-272del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00993 in 152,096 control chromosomes in the GnomAD database, including 16 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0099 (16 hom., cov: 32)
• Consequence: F12 ENST00000253496.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.943

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.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00993 (1511/152096) while in subpopulation NFE AF= 0.0171 (1164/67960). AF 95% confidence interval is 0.0163. There are 16 homozygotes in gnomad4. There are 703 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F12	NM_000505.4	c.116-272del		intron_variant		ENST00000253496.4	NP_000496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4	c.116-272del		intron_variant		1	NM_000505.4	ENSP00000253496	P1

Frequencies

GnomAD3 genomes AF: 0.00995 AC: 1512 AN: 151978 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00501

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0105

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

GnomAD4 genome AF: 0.00993 AC: 1511 AN: 152096 Hom.: 16 Cov.: 32 AF XY: 0.00945 AC XY: 703 AN XY: 74356

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00501

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00424 Hom.: 0

Bravo AF: 0.00965

ClinVar

Not reported in ClinVar

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: rs41309744; hg19: chr5-176833333;