rs41309760

Variant names:

• chr5-177403740-G-A
• rs41309760
• NM_000505.4:c.1250+119C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-177403740-G-A
• chr5-177403740-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 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
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00551 (839/152342) while in subpopulation NFE AF = 0.00763 (519/68028). AF 95% confidence interval is 0.00709. There are 5 homozygotes in GnomAd4. There are 416 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F12	NM_000505.4	c.1250+119C>T		intron_variant	Intron 10 of 13	ENST00000253496.4	NP_000496.2
F12	XM_011534462.3	c.914+119C>T		intron_variant	Intron 7 of 10		XP_011532764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4	c.1250+119C>T		intron_variant	Intron 10 of 13	1	NM_000505.4	ENSP00000253496.3

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

African (AFR) AF: 0.000683 AC: 21 AN: 30736

American (AMR) AF: 0.00416 AC: 141 AN: 33862

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 282 AN: 22280

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35602

South Asian (SAS) AF: 0.00281 AC: 206 AN: 73354

European-Finnish (FIN) AF: 0.00622 AC: 207 AN: 33304

Middle Eastern (MID) AF: 0.00673 AC: 26 AN: 3862

European-Non Finnish (NFE) AF: 0.00710 AC: 7390 AN: 1040348

Other (OTH) AF: 0.00632 AC: 349 AN: 55252

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

African (AFR) AF: 0.00144 AC: 60 AN: 41578

American (AMR) AF: 0.00633 AC: 97 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4832

European-Finnish (FIN) AF: 0.00819 AC: 87 AN: 10622

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00763 AC: 519 AN: 68028

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

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
PhyloP100		3.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs41309760; hg19: chr5-176830741;