chr5-177406316-C-A

Variant names:

• chr5-177406316-C-A
• rs7709674
• NM_000505.4:c.116-255G>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000505.4(F12):​c.116-255G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 152,116 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.076 (620 hom., cov: 32)
• Consequence: F12 NM_000505.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.46

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 5-177406316-C-A is Benign according to our data. Variant chr5-177406316-C-A is described in ClinVar as [Benign]. Clinvar id is 1234893.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F12	NM_000505.4	c.116-255G>T		intron_variant	Intron 2 of 13	ENST00000253496.4	NP_000496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4	c.116-255G>T		intron_variant	Intron 2 of 13	1	NM_000505.4	ENSP00000253496.3

Frequencies

GnomAD3 genomes AF: 0.0763 AC: 11591 AN: 151998 Hom.: 619 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0458

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0681

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0763 AC: 11610 AN: 152116 Hom.: 620 Cov.: 32 AF XY: 0.0783 AC XY: 5827 AN XY: 74374

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0375

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.0458

Gnomad4 NFE AF: 0.0394

Gnomad4 OTH AF: 0.0669

Alfa AF: 0.0226 Hom.: 11

Bravo AF: 0.0784

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.20
DANN	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs7709674; hg19: chr5-176833317;