5-177404588-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000505.4(F12):c.711C>T(p.Pro237Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,608,338 control chromosomes in the GnomAD database, including 749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 62 hom., cov: 33)

Exomes 𝑓: 0.028 ( 687 hom. )

Consequence

F12
NM_000505.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.389

Publications

7 publications found

Variant links:

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]

F12 links:

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]

GRK6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 5-177404588-G-A is Benign according to our data. Variant chr5-177404588-G-A is described in ClinVar as Benign. ClinVar VariationId is 352999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.389 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0229 (3491/152214) while in subpopulation NFE AF = 0.0321 (2184/67974). AF 95% confidence interval is 0.031. There are 62 homozygotes in GnomAd4. There are 1727 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 62 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	NM_000505.4	MANE Select	c.711C>T	p.Pro237Pro	synonymous	Exon 8 of 14	NP_000496.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
F12	ENST00000253496.4	TSL:1 MANE Select	c.711C>T	p.Pro237Pro	synonymous	Exon 8 of 14	ENSP00000253496.3
F12	ENST00000696201.1		c.711C>T	p.Pro237Pro	synonymous	Exon 8 of 14	ENSP00000512482.1
F12	ENST00000696192.1		n.*377C>T		non_coding_transcript_exon	Exon 8 of 14	ENSP00000512476.1

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3493

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0192

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0609

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0321

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0228

AC:

5347

AN:

234774

AF XY:

0.0232

show subpopulations

Gnomad AFR exome

AF:

0.00436

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.0257

Gnomad EAS exome

AF:

0.0000574

Gnomad FIN exome

AF:

0.0561

Gnomad NFE exome

AF:

0.0321

Gnomad OTH exome

AF:

0.0231

GnomAD4 exome

AF:

0.0280

AC:

40755

AN:

1456124

Hom.:

687

Cov.:

AF XY:

0.0272

AC XY:

19700

AN XY:

724486

show subpopulations

African (AFR)

AF:

0.00403

AC:

135

AN:

33462

American (AMR)

AF:

0.0134

AC:

595

AN:

44454

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

646

AN:

26044

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39640

South Asian (SAS)

AF:

0.00317

AC:

273

AN:

86004

European-Finnish (FIN)

AF:

0.0543

AC:

2679

AN:

49342

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0314

AC:

34862

AN:

1111212

Other (OTH)

AF:

0.0246

AC:

1478

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

2492

4984

7475

9967

12459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1254

2508

3762

5016

6270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0229

AC:

3491

AN:

152214

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1727

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00484

AC:

201

AN:

41560

American (AMR)

AF:

0.0192

AC:

294

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.00331

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0609

AC:

646

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0321

AC:

2184

AN:

67974

Other (OTH)

AF:

0.0289

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

175

349

524

698

873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0262

Hom.:

181

Bravo

AF:

0.0196

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary angioedema type 3 (2)

not provided (2)

Factor XII deficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.2

(source)

DANN

Benign

0.83

PhyloP100

-0.39

PromoterAI

0.018

Neutral

(source)

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over