rs17876030

Variant names:

• chr5-177404825-C-G
• rs17876030
• NM_000505.4:c.619G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-177404825-C-G
• chr5-177404825-C-A
• chr5-177404825-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000505.4(F12):​c.619G>C​(p.Ala207Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.977 in 1,607,244 control chromosomes in the GnomAD database, including 767,374 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70890 hom., cov: 31)
  • Exomes 𝑓: 0.98 (696484 hom.)
• Consequence: F12 NM_000505.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.217
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1377568E-6).
• BP6: Variant 5-177404825-C-G is Benign according to our data. Variant chr5-177404825-C-G is described in ClinVar as Benign. ClinVar VariationId is 256310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

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.619G>C	p.Ala207Pro	missense	Exon 7 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.619G>C	p.Ala207Pro	missense	Exon 7 of 14	ENSP00000253496.3	P00748
	F12	ENST00000898128.1		c.694G>C	p.Ala232Pro	missense	Exon 8 of 15	ENSP00000568187.1
	F12	ENST00000898127.1		c.662G>C	p.Ser221Thr	missense	Exon 6 of 13	ENSP00000568186.1

Frequencies

GnomAD3 genomes AF: 0.964 AC: 146685 AN: 152086 Hom.: 70852 Cov.: 31

Gnomad AFR AF: 0.959

Gnomad AMI AF: 0.883

Gnomad AMR AF: 0.884

Gnomad ASJ AF: 0.990

Gnomad EAS AF: 0.897

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.989

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.967

GnomAD2 exomes AF: 0.949 AC: 225306 AN: 237422 AF XY: 0.955

Gnomad AFR exome AF: 0.959

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.987

Gnomad EAS exome AF: 0.886

Gnomad FIN exome AF: 0.989

Gnomad NFE exome AF: 0.987

Gnomad OTH exome AF: 0.958

GnomAD4 exome AF: 0.978 AC: 1422839 AN: 1455040 Hom.: 696484 Cov.: 56 AF XY: 0.978 AC XY: 707450 AN XY: 723492

African (AFR) AF: 0.955 AC: 31816 AN: 33324

American (AMR) AF: 0.822 AC: 36114 AN: 43924

Ashkenazi Jewish (ASJ) AF: 0.987 AC: 25678 AN: 26026

East Asian (EAS) AF: 0.915 AC: 36023 AN: 39384

South Asian (SAS) AF: 0.958 AC: 81840 AN: 85444

European-Finnish (FIN) AF: 0.989 AC: 51149 AN: 51716

Middle Eastern (MID) AF: 0.966 AC: 5000 AN: 5174

European-Non Finnish (NFE) AF: 0.988 AC: 1096727 AN: 1109994

Other (OTH) AF: 0.974 AC: 58492 AN: 60054

GnomAD4 genome AF: 0.964 AC: 146777 AN: 152204 Hom.: 70890 Cov.: 31 AF XY: 0.962 AC XY: 71601 AN XY: 74412

African (AFR) AF: 0.959 AC: 39829 AN: 41530

American (AMR) AF: 0.883 AC: 13510 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.990 AC: 3436 AN: 3472

East Asian (EAS) AF: 0.896 AC: 4616 AN: 5150

South Asian (SAS) AF: 0.956 AC: 4604 AN: 4818

European-Finnish (FIN) AF: 0.989 AC: 10495 AN: 10612

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.988 AC: 67161 AN: 68010

Other (OTH) AF: 0.963 AC: 2031 AN: 2108

Alfa AF: 0.981 Hom.: 23697

Bravo AF: 0.954

TwinsUK AF: 0.988 AC: 3663

ALSPAC AF: 0.987 AC: 3803

ESP6500AA AF: 0.960 AC: 4218

ESP6500EA AF: 0.986 AC: 8470

ExAC AF: 0.954 AC: 115051

Asia WGS AF: 0.924 AC: 3216 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Hereditary angioedema type 3 (3)
-	-	2	not provided (2)
-	-	1	Factor XII deficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.3
DANN	Benign	0.29
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.042	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.82	N
PhyloP100		0.22
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.098
Sift	Benign	0.31	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.045
MPC		0.98
ClinPred		0.014	T
GERP RS		2.1
PromoterAI		0.014	Neutral
Varity_R		0.093
gMVP		0.83
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: rs17876030; hg19: chr5-176831826; COSMIC: COSV53692430; COSMIC: COSV53692430;