rs17876033

Variant names:

• chr5-177403569-G-A
• rs17876033
• NM_000505.4:c.1299C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000505.4(F12):​c.1299C>T​(p.Asn433Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,604,796 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (7 hom.)
• Consequence: F12 NM_000505.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.197
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 5-177403569-G-A is Benign according to our data. Variant chr5-177403569-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 352987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.197 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000899 (137/152354) while in subpopulation NFE AF = 0.00154 (105/68030). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	NM_000505.4	MANE Select	c.1299C>T	p.Asn433Asn	synonymous	Exon 11 of 14	NP_000496.2	P00748

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	ENST00000253496.4	TSL:1 MANE Select	c.1299C>T	p.Asn433Asn	synonymous	Exon 11 of 14	ENSP00000253496.3	P00748
	F12	ENST00000898128.1		c.1374C>T	p.Asn458Asn	synonymous	Exon 12 of 15	ENSP00000568187.1
	F12	ENST00000898127.1		c.1287C>T	p.Asn429Asn	synonymous	Exon 10 of 13	ENSP00000568186.1

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000863 AC: 202 AN: 234022 AF XY: 0.000863

Gnomad AFR exome AF: 0.000347

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000594

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.000519

GnomAD4 exome AF: 0.00163 AC: 2362 AN: 1452442 Hom.: 7 Cov.: 31 AF XY: 0.00159 AC XY: 1150 AN XY: 722546

African (AFR) AF: 0.000300 AC: 10 AN: 33314

American (AMR) AF: 0.000995 AC: 44 AN: 44232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85460

European-Finnish (FIN) AF: 0.0000622 AC: 3 AN: 48266

Middle Eastern (MID) AF: 0.000569 AC: 3 AN: 5270

European-Non Finnish (NFE) AF: 0.00199 AC: 2211 AN: 1110408

Other (OTH) AF: 0.00150 AC: 90 AN: 60066

GnomAD4 genome AF: 0.000899 AC: 137 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74502

African (AFR) AF: 0.000457 AC: 19 AN: 41588

American (AMR) AF: 0.000718 AC: 11 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68030

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000854

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	F12-related disorder (1)
-	-	1	Factor XII deficiency disease (1)
-	-	1	Hereditary angioedema type 3 (1)
-	-	1	Hereditary angioneurotic edema (1)
-	-	1	Nephrolithiasis/osteoporosis, hypophosphatemic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.8
DANN	Benign	0.92
PhyloP100		0.20
PromoterAI		0.013	Neutral
Mutation Taster		=100/0	polymorphism

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: rs17876033; hg19: chr5-176830570;