rs17876032

Variant names:

• chr5-177403626-G-A
• rs17876032
• NM_000505.4:c.1251-9C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-177403626-G-A
• chr5-177403626-G-C
• chr5-177403626-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000505.4(F12):​c.1251-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,600,484 control chromosomes in the GnomAD database, including 296,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (21090 hom., cov: 33)
  • Exomes 𝑓: 0.60 (275054 hom.)
• Consequence: F12 NM_000505.4 intron
• Scores: Splicing: ADA: 0.00001529
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.732
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-177403626-G-A is Benign according to our data. Variant chr5-177403626-G-A is described in ClinVar as Benign. ClinVar VariationId is 256309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.642 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.1251-9C>T		intron	N/A	NP_000496.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	ENST00000253496.4	TSL:1 MANE Select	c.1251-9C>T		intron	N/A	ENSP00000253496.3
	F12	ENST00000898128.1		c.1326-9C>T		intron	N/A	ENSP00000568187.1
	F12	ENST00000898127.1		c.1239-9C>T		intron	N/A	ENSP00000568186.1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71788 AN: 152016 Hom.: 21097 Cov.: 33

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.529

GnomAD2 exomes AF: 0.517 AC: 120945 AN: 233808 AF XY: 0.531

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.365

Gnomad ASJ exome AF: 0.678

Gnomad EAS exome AF: 0.225

Gnomad FIN exome AF: 0.687

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.578

GnomAD4 exome AF: 0.603 AC: 873388 AN: 1448350 Hom.: 275054 Cov.: 68 AF XY: 0.600 AC XY: 432178 AN XY: 720510

African (AFR) AF: 0.117 AC: 3897 AN: 33332

American (AMR) AF: 0.382 AC: 16968 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 17643 AN: 26074

East Asian (EAS) AF: 0.269 AC: 10619 AN: 39518

South Asian (SAS) AF: 0.409 AC: 35150 AN: 85960

European-Finnish (FIN) AF: 0.679 AC: 30373 AN: 44748

Middle Eastern (MID) AF: 0.629 AC: 2727 AN: 4334

European-Non Finnish (NFE) AF: 0.650 AC: 721918 AN: 1110078

Other (OTH) AF: 0.569 AC: 34093 AN: 59898

GnomAD4 genome AF: 0.472 AC: 71781 AN: 152134 Hom.: 21090 Cov.: 33 AF XY: 0.472 AC XY: 35084 AN XY: 74368

African (AFR) AF: 0.138 AC: 5715 AN: 41542

American (AMR) AF: 0.493 AC: 7536 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2345 AN: 3470

East Asian (EAS) AF: 0.224 AC: 1156 AN: 5154

South Asian (SAS) AF: 0.384 AC: 1850 AN: 4822

European-Finnish (FIN) AF: 0.690 AC: 7311 AN: 10598

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43984 AN: 67946

Other (OTH) AF: 0.527 AC: 1112 AN: 2112

Alfa AF: 0.595 Hom.: 51878

Bravo AF: 0.444

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Hereditary angioedema type 3 (2)
-	-	2	not provided (2)
-	-	1	Factor XII deficiency disease (1)
-	-	1	Hereditary angioneurotic edema (1)
-	-	1	Nephrolithiasis/osteoporosis, hypophosphatemic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.2
DANN	Benign	0.82
PhyloP100		0.73
PromoterAI		-0.040	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0040
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: rs17876032; hg19: chr5-176830627; COSMIC: COSV53689991; COSMIC: COSV53689991;