chr5-177402410-C-A

Variant names:

• chr5-177402410-C-A
• NM_000505.4:c.1730G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000505.4(F12):​c.1730G>T​(p.Arg577Leu) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: F12 NM_000505.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.458

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Coagulation factor XIIa light chain (size 242) 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F12	NM_000505.4	c.1730G>T	p.Arg577Leu	missense_variant	Exon 14 of 14	ENST00000253496.4	NP_000496.2
F12	XM_011534462.3	c.1394G>T	p.Arg465Leu	missense_variant	Exon 11 of 11		XP_011532764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4	c.1730G>T	p.Arg577Leu	missense_variant	Exon 14 of 14	1	NM_000505.4	ENSP00000253496.3

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

Inborn genetic diseases Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1730G>T (p.R577L) alteration is located in exon 14 (coding exon 14) of the F12 gene. This alteration results from a G to T substitution at nucleotide position 1730, causing the arginine (R) at amino acid position 577 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.029	D
Sift4G	Benign	0.15	T
Polyphen		0.91	P
Vest4		0.23
MutPred		0.75		Loss of disorder (P = 0.1054);
MVP		0.80
MPC		0.52
ClinPred		0.64	D
GERP RS		-0.074
Varity_R		0.33
gMVP		0.72

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-176829411;