NM_000505.4:c.1530G>C

Variant names:

• chr5-177403255-C-G
• rs1763185944
• NM_000505.4:c.1530G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000505.4(F12):​c.1530G>C​(p.Glu510Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: F12 NM_000505.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001222
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.50
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1530G>C	p.Glu510Asp	missense splice_region	Exon 12 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.1530G>C	p.Glu510Asp	missense splice_region	Exon 12 of 14	ENSP00000253496.3	P00748
	F12	ENST00000898128.1		c.1605G>C	p.Glu535Asp	missense splice_region	Exon 13 of 15	ENSP00000568187.1
	F12	ENST00000898127.1		c.1518G>C	p.Glu506Asp	missense splice_region	Exon 11 of 13	ENSP00000568186.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary angioedema type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	-0.13	N
PhyloP100		-1.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.42		Loss of disorder (P = 0.1306)
MVP		0.95
MPC		0.41
ClinPred		0.87	D
GERP RS		-1.7
PromoterAI		-0.016	Neutral
Varity_R		0.84
gMVP		0.62
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.14
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: rs1763185944; hg19: chr5-176830256;