NM_000505.4:c.57+46G>T

Variant names:

• chr5-177409425-C-A
• rs4314418
• NM_000505.4:c.57+46G>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.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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.338
• Publications: 6 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=-0.8).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000505.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	NM_000505.4	MANE Select	c.57+46G>T		intron	N/A	NP_000496.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	ENST00000253496.4	TSL:1 MANE Select	c.57+46G>T		intron	N/A	ENSP00000253496.3
	F12	ENST00000696201.1		c.57+46G>T		intron	N/A	ENSP00000512482.1
	GRK6	ENST00000506296.5	TSL:5	c.-45+4868C>A		intron	N/A	ENSP00000421055.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1922 AN: 152010 Hom.: 21 Cov.: 32

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

GnomAD2 exomes AF: 0.0159 AC: 3944 AN: 247468 AF XY: 0.0179

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 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.: 29 AF XY: 0.0197 AC XY: 14213 AN XY: 720676

African (AFR) AF: 0.00256 AC: 85 AN: 33212

American (AMR) AF: 0.00647 AC: 288 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 347 AN: 25990

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39590

South Asian (SAS) AF: 0.0385 AC: 3295 AN: 85648

European-Finnish (FIN) AF: 0.00506 AC: 268 AN: 53010

Middle Eastern (MID) AF: 0.0352 AC: 202 AN: 5740

European-Non Finnish (NFE) AF: 0.0202 AC: 22191 AN: 1100002

Other (OTH) AF: 0.0171 AC: 1025 AN: 59884

GnomAD4 genome AF: 0.0126 AC: 1921 AN: 152128 Hom.: 21 Cov.: 32 AF XY: 0.0125 AC XY: 931 AN XY: 74372

African (AFR) AF: 0.00328 AC: 136 AN: 41498

American (AMR) AF: 0.0113 AC: 172 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0383 AC: 184 AN: 4810

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0190 AC: 1290 AN: 67966

Other (OTH) AF: 0.0156 AC: 33 AN: 2110

Alfa AF: 0.0167 Hom.: 11

Bravo AF: 0.0124

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.8
DANN	Benign	0.72
PhyloP100		-0.34
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4314418; hg19: chr5-176836426;