5-177403626-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000505.4(F12):c.1251-9C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 1,600,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: F12 NM_000505.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002085
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.732

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-177403626-G-C is Benign according to our data. Variant chr5-177403626-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2890717.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177403626-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F12	NM_000505.4	c.1251-9C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000253496.4
F12	XM_011534462.3	c.915-9C>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F12	ENST00000253496.4	c.1251-9C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000505.4	P1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152042 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000927

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000616 AC: 144 AN: 233808 Hom.: 0 AF XY: 0.000519 AC XY: 67 AN XY: 129002

Gnomad AFR exome AF: 0.000281

Gnomad AMR exome AF: 0.000884

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000990

Gnomad FIN exome AF: 0.000401

Gnomad NFE exome AF: 0.000830

Gnomad OTH exome AF: 0.00207

GnomAD4 exome AF: 0.000670 AC: 970 AN: 1448504 Hom.: 0 Cov.: 68 AF XY: 0.000631 AC XY: 455 AN XY: 720590

Gnomad4 AFR exome AF: 0.000390

Gnomad4 AMR exome AF: 0.000900

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.000647

Gnomad4 NFE exome AF: 0.000753

Gnomad4 OTH exome AF: 0.000634

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152160 Hom.: 1 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74384

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000927

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000610 Hom.: 35918

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	5.1
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.010		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: rs17876032; hg19: chr5-176830627;