rs41309752

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000505.4(F12):c.756C>T(p.Ala252Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 1,603,096 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 69 hom., cov: 33)

Exomes 𝑓: 0.0076 ( 192 hom. )

Consequence

F12
NM_000505.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.08

Publications

4 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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new If you want to explore the variant's impact on the transcript NM_000505.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.7).

BP6

Variant 5-177404543-G-A is Benign according to our data. Variant chr5-177404543-G-A is described in ClinVar as Benign. ClinVar VariationId is 352998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.08 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0509 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.756C>T	p.Ala252Ala	synonymous	Exon 8 of 14	NP_000496.2	P00748

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
F12	ENST00000253496.4	TSL:1 MANE Select	c.756C>T	p.Ala252Ala	synonymous	Exon 8 of 14	ENSP00000253496.3	P00748
F12	ENST00000898128.1		c.831C>T	p.Ala277Ala	synonymous	Exon 9 of 15	ENSP00000568187.1
F12	ENST00000898127.1		c.744C>T	p.Ala248Ala	synonymous	Exon 7 of 13	ENSP00000568186.1

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3012

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0527

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0422

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0318

Gnomad NFE

AF:

0.00470

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0133

AC:

2953

AN:

221280

AF XY:

0.0149

show subpopulations

Gnomad AFR exome

AF:

0.0565

Gnomad AMR exome

AF:

0.00775

Gnomad ASJ exome

AF:

0.0229

Gnomad EAS exome

AF:

0.000244

Gnomad FIN exome

AF:

0.000595

Gnomad NFE exome

AF:

0.00491

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.00762

AC:

11055

AN:

1450816

Hom.:

192

Cov.:

AF XY:

0.00876

AC XY:

6316

AN XY:

721100

show subpopulations

African (AFR)

AF:

0.0544

AC:

1815

AN:

33366

American (AMR)

AF:

0.00865

AC:

372

AN:

43020

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

572

AN:

25814

East Asian (EAS)

AF:

0.000407

AC:

AN:

39342

South Asian (SAS)

AF:

0.0411

AC:

3496

AN:

85144

European-Finnish (FIN)

AF:

0.000671

AC:

AN:

50666

Middle Eastern (MID)

AF:

0.0302

AC:

174

AN:

5756

European-Non Finnish (NFE)

AF:

0.00347

AC:

3841

AN:

1107792

Other (OTH)

AF:

0.0123

AC:

735

AN:

59916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

722

1444

2165

2887

3609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.0198

AC:

3016

AN:

152280

Hom.:

Cov.:

AF XY:

0.0193

AC XY:

1435

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0528

AC:

2193

AN:

41558

American (AMR)

AF:

0.0109

AC:

167

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0414

AC:

200

AN:

4830

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00470

AC:

320

AN:

68014

Other (OTH)

AF:

0.0218

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

148

296

443

591

739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0125

Hom.:

Bravo

AF:

0.0212

Asia WGS

AF:

0.0320

AC:

113

AN:

3478

ClinVar

ClinVar submissions

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

-0.70

CADD

Benign

2.5

(source)

DANN

Benign

0.92

PhyloP100

-2.1

PromoterAI

0.059

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over