rs4976692

Variant names:

• chr5-177406305-A-G
• rs4976692
• NM_000505.4:c.116-244T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-177406305-A-G
• chr5-177406305-A-C
• chr5-177406305-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000505.4(F12):​c.116-244T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 151,782 control chromosomes in the GnomAD database, including 6,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.28 (6063 hom., cov: 32)
• Consequence: F12 NM_000505.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.231
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 5-177406305-A-G is Benign according to our data. Variant chr5-177406305-A-G is described in ClinVar as Benign. ClinVar VariationId is 1243824.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

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.116-244T>C		intron	N/A	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.116-244T>C		intron	N/A	ENSP00000253496.3	P00748
	F12	ENST00000898128.1		c.116-244T>C		intron	N/A	ENSP00000568187.1
	F12	ENST00000898127.1		c.116-244T>C		intron	N/A	ENSP00000568186.1

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41731 AN: 151662 Hom.: 6055 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.248

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

GnomAD4 genome AF: 0.275 AC: 41761 AN: 151782 Hom.: 6063 Cov.: 32 AF XY: 0.281 AC XY: 20840 AN XY: 74182

African (AFR) AF: 0.263 AC: 10898 AN: 41400

American (AMR) AF: 0.236 AC: 3594 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 695 AN: 3468

East Asian (EAS) AF: 0.486 AC: 2500 AN: 5140

South Asian (SAS) AF: 0.477 AC: 2298 AN: 4814

European-Finnish (FIN) AF: 0.283 AC: 2985 AN: 10546

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18095 AN: 67848

Other (OTH) AF: 0.252 AC: 530 AN: 2104

Alfa AF: 0.156 Hom.: 299

Bravo AF: 0.267

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.56
DANN	Benign	0.44
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

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: rs4976692; hg19: chr5-176833306;