5-177403255-C-G

Position:

• chr5-177403255-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 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

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Peptidase S1 (size 241) in uniprot entity FA12_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_000505.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F12	NM_000505.4	c.1530G>C	p.Glu510Asp	missense_variant, splice_region_variant	12/14	ENST00000253496.4	NP_000496.2
F12	XM_011534462.3	c.1194G>C	p.Glu398Asp	missense_variant, splice_region_variant	9/11		XP_011532764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4	c.1530G>C	p.Glu510Asp	missense_variant, splice_region_variant	12/14	1	NM_000505.4	ENSP00000253496	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary angioedema type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeMIA

-

The c.1530G>C (p.Glu510Asp) variant, located in exon 12 of the F12 gene, was identified in a 12-year old girl with hereditary angioedema presenting with five to six angioedema attacks per month located in the face. Family segregation study performed in the family revealed the mutation in three healthy family members (two males and one female). Bioinformatic analysis by SIFT and PolyPhen2 algorithms predicted this mutation as probably damaging. It was not detected amongst 125,748 exomes and 15,708 genomes of the Genome Aggregation Database (gnomAD), indicating that it is not a common variant. Taking all the above into account and according to ACMG Guidelines (Criteria: PM2, PP3, BS2) the variant is considered as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.78	N
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
Varity_R		0.84
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs1763185944; hg19: chr5-176830256;