rs118204456

Variant names:

• chr5-177404231-G-C
• rs118204456
• NM_000505.4:c.983C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-177404231-G-C
• chr5-177404231-G-T
• chr5-177404231-G-A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000505.4(F12):​c.983C>G​(p.Thr328Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T328K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: F12 NM_000505.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.61
• Publications: 51 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-177404231-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 5-177404231-G-C is Pathogenic according to our data. Variant chr5-177404231-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1170.Status of the report is criteria_provided_single_submitter, 1 stars.

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.983C>G	p.Thr328Arg	missense	Exon 9 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.983C>G	p.Thr328Arg	missense	Exon 9 of 14	ENSP00000253496.3	P00748
	F12	ENST00000898128.1		c.1058C>G	p.Thr353Arg	missense	Exon 10 of 15	ENSP00000568187.1
	F12	ENST00000898127.1		c.971C>G	p.Thr324Arg	missense	Exon 8 of 13	ENSP00000568186.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Angioedema;C0020538:Hypertensive disorder;C0042109:Urticaria;C0311468:Hyperbilirubinemia (1)
1	-	-	Factor XII deficiency disease (1)
1	-	-	Hereditary angioedema type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.51
Sift	Benign	0.058	T
Sift4G	Benign	0.23	T
Polyphen		0.97	D
Vest4		0.76
MutPred		0.74		Loss of glycosylation at T328 (P = 0.0013)
MVP		0.95
MPC		1.8
ClinPred		0.53	D
GERP RS		4.1
PromoterAI		-0.062	Neutral
Varity_R		0.095
gMVP		0.76
Mutation Taster		=50/50	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: rs118204456; hg19: chr5-176831232;