Variant rs4314418 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000505.4(F12):c.57+46G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,599,702 control chromosomes in the GnomAD database, including 372 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 0.013 ( 21 hom., cov: 32)

Exomes 𝑓: 0.019 ( 351 hom. )

Consequence

F12
NM_000505.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.338

Variant links:

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]

F12 links:

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]

GRK6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0126 (1921/152128) while in subpopulation SAS AF= 0.0383 (184/4810). AF 95% confidence interval is 0.0337. There are 21 homozygotes in gnomad4. There are 931 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F12	NM_000505.4 link	c.57+46G>T		intron_variant		ENST00000253496.4	NP_000496.2	P00748Q8IZZ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4 link	c.57+46G>T		intron_variant		1	NM_000505.4	ENSP00000253496.3		P00748

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1922

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00329

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0384

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0159

AC:

3944

AN:

247468

Hom.:

AF XY:

0.0179

AC XY:

2393

AN XY:

133788

show subpopulations

Gnomad AFR exome

AF:

0.00329

Gnomad AMR exome

AF:

0.00572

Gnomad ASJ exome

AF:

0.0140

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.0399

Gnomad FIN exome

AF:

0.00514

Gnomad NFE exome

AF:

0.0192

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0191

AC:

27703

AN:

1447574

Hom.:

351

Cov.:

AF XY:

0.0197

AC XY:

14213

AN XY:

720676

show subpopulations

Gnomad4 AFR exome

AF:

0.00256

Gnomad4 AMR exome

AF:

0.00647

Gnomad4 ASJ exome

AF:

0.0134

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0385

Gnomad4 FIN exome

AF:

0.00506

Gnomad4 NFE exome

AF:

0.0202

Gnomad4 OTH exome

AF:

0.0171

GnomAD4 genome

AF:

0.0126

AC:

1921

AN:

152128

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

931

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00328

Gnomad4 AMR

AF:

0.0113

Gnomad4 ASJ

AF:

0.0170

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0383

Gnomad4 FIN

AF:

0.00349

Gnomad4 NFE

AF:

0.0190

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0163

Hom.:

Bravo

AF:

0.0124

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.8

DANN

Benign

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over