5-177403626-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS1

The NM_000505.4(F12):c.1251-9C>G variant causes a 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 intron

Scores

Splicing: ADA: 0.0002085

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.732

Publications

17 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 -10 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 VariationId is 2890717.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000572 (87/152160) while in subpopulation NFE AF = 0.000927 (63/67950). AF 95% confidence interval is 0.000743. There are 1 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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>G		intron	N/A	NP_000496.2	P00748

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
F12	ENST00000253496.4	TSL:1 MANE Select	c.1251-9C>G	intron	N/A	ENSP00000253496.3	P00748
F12	ENST00000898128.1		c.1326-9C>G	intron	N/A	ENSP00000568187.1
F12	ENST00000898127.1		c.1239-9C>G	intron	N/A	ENSP00000568186.1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000616

AC:

144

AN:

233808

AF XY:

0.000519

show subpopulations

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 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.:

Cov.:

AF XY:

0.000631

AC XY:

455

AN XY:

720590

show subpopulations

African (AFR)

AF:

0.000390

AC:

AN:

33332

American (AMR)

AF:

0.000900

AC:

AN:

44426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39522

South Asian (SAS)

AF:

0.000140

AC:

AN:

85970

European-Finnish (FIN)

AF:

0.000647

AC:

AN:

44788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4336

European-Non Finnish (NFE)

AF:

0.000753

AC:

836

AN:

1110152

Other (OTH)

AF:

0.000634

AC:

AN:

59902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<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:

0.000572

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41554

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000927

AC:

AN:

67950

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000403

Hom.:

51878

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.1

(source)

DANN

Benign

0.53

PhyloP100

0.73

PromoterAI

-0.085

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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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