rs183643295

Variant names:

• chr5-177404082-C-G
• rs183643295
• NM_000505.4:c.1027G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000505.4(F12):​c.1027G>C​(p.Ala343Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,602,464 control chromosomes in the GnomAD database, including 37 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (32 hom.)
• Consequence: F12 NM_000505.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: -0.0910
• Publications: 8 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=0.0036440194).
• BP6: Variant 5-177404082-C-G is Benign according to our data. Variant chr5-177404082-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 225352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00145 (221/152366) while in subpopulation EAS AF = 0.028 (145/5174). AF 95% confidence interval is 0.0243. There are 5 homozygotes in GnomAd4. There are 129 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

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.1027G>C	p.Ala343Pro	missense	Exon 10 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.1027G>C	p.Ala343Pro	missense	Exon 10 of 14	ENSP00000253496.3	P00748
	F12	ENST00000898128.1		c.1102G>C	p.Ala368Pro	missense	Exon 11 of 15	ENSP00000568187.1
	F12	ENST00000898127.1		c.1015G>C	p.Ala339Pro	missense	Exon 9 of 13	ENSP00000568186.1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152248 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00315 AC: 701 AN: 222724 AF XY: 0.00283

Gnomad AFR exome AF: 0.0000746

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0347

Gnomad FIN exome AF: 0.00489

Gnomad NFE exome AF: 0.0000406

Gnomad OTH exome AF: 0.000543

GnomAD4 exome AF: 0.00144 AC: 2093 AN: 1450098 Hom.: 32 Cov.: 33 AF XY: 0.00143 AC XY: 1030 AN XY: 721632

African (AFR) AF: 0.0000897 AC: 3 AN: 33446

American (AMR) AF: 0.0000226 AC: 1 AN: 44320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.0433 AC: 1712 AN: 39582

South Asian (SAS) AF: 0.000501 AC: 43 AN: 85812

European-Finnish (FIN) AF: 0.00411 AC: 182 AN: 44336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1110752

Other (OTH) AF: 0.00185 AC: 111 AN: 60090

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152366 Hom.: 5 Cov.: 33 AF XY: 0.00173 AC XY: 129 AN XY: 74514

African (AFR) AF: 0.0000962 AC: 4 AN: 41592

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0280 AC: 145 AN: 5174

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.00130

ExAC AF: 0.00281 AC: 336

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	3	Factor XII deficiency disease (4)
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	F12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	3.2
DANN	Benign	0.87
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.091
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.20
Sift	Uncertain	0.027	D
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.70
MPC		1.1
ClinPred		0.011	T
GERP RS		-4.8
PromoterAI		0.0078	Neutral
Varity_R		0.093
gMVP		0.50
Mutation Taster		=92/8	disease causing (ClinVar)

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: rs183643295; hg19: chr5-176831083;