GeneBe

rs6018

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000130.5(F5):​c.2450A>C​(p.Asn817Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0611 in 1,613,968 control chromosomes in the GnomAD database, including 3,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 357 hom., cov: 32)
Exomes 𝑓: 0.062 ( 3182 hom. )

Consequence

F5
NM_000130.5 missense

Scores

4
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.208
Variant links:
Genes affected
F5 (HGNC:3542): (coagulation factor V) This gene encodes an essential cofactor of the blood coagulation cascade. This factor circulates in plasma, and is converted to the active form by the release of the activation peptide by thrombin during coagulation. This generates a heavy chain and a light chain which are held together by calcium ions. The activated protein is a cofactor that participates with activated coagulation factor X to activate prothrombin to thrombin. Defects in this gene result in either an autosomal recessive hemorrhagic diathesis or an autosomal dominant form of thrombophilia, which is known as activated protein C resistance. [provided by RefSeq, Oct 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0034109354).
BP6
Variant 1-169542640-T-G is Benign according to our data. Variant chr1-169542640-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 255199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169542640-T-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0979 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
F5NM_000130.5 linkc.2450A>C p.Asn817Thr missense_variant Exon 13 of 25 ENST00000367797.9 NP_000121.2 P12259

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
F5ENST00000367797.9 linkc.2450A>C p.Asn817Thr missense_variant Exon 13 of 25 1 NM_000130.5 ENSP00000356771.3 P12259
F5ENST00000367796.3 linkc.2465A>C p.Asn822Thr missense_variant Exon 13 of 25 5 ENSP00000356770.3 A0A0A0MRJ7

Frequencies

GnomAD3 genomes
AF:
0.0550
AC:
8356
AN:
152026
Hom.:
356
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0111
Gnomad AMI
AF:
0.00329
Gnomad AMR
AF:
0.102
Gnomad ASJ
AF:
0.0750
Gnomad EAS
AF:
0.0299
Gnomad SAS
AF:
0.0730
Gnomad FIN
AF:
0.0839
Gnomad MID
AF:
0.0823
Gnomad NFE
AF:
0.0664
Gnomad OTH
AF:
0.0675
GnomAD3 exomes
AF:
0.0654
AC:
16423
AN:
251256
Hom.:
677
AF XY:
0.0662
AC XY:
8983
AN XY:
135790
show subpopulations
Gnomad AFR exome
AF:
0.00898
Gnomad AMR exome
AF:
0.0957
Gnomad ASJ exome
AF:
0.0699
Gnomad EAS exome
AF:
0.0303
Gnomad SAS exome
AF:
0.0741
Gnomad FIN exome
AF:
0.0855
Gnomad NFE exome
AF:
0.0628
Gnomad OTH exome
AF:
0.0742
GnomAD4 exome
AF:
0.0618
AC:
90317
AN:
1461824
Hom.:
3182
Cov.:
54
AF XY:
0.0626
AC XY:
45535
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00908
Gnomad4 AMR exome
AF:
0.0962
Gnomad4 ASJ exome
AF:
0.0705
Gnomad4 EAS exome
AF:
0.0599
Gnomad4 SAS exome
AF:
0.0738
Gnomad4 FIN exome
AF:
0.0835
Gnomad4 NFE exome
AF:
0.0597
Gnomad4 OTH exome
AF:
0.0619
GnomAD4 genome
AF:
0.0549
AC:
8358
AN:
152144
Hom.:
357
Cov.:
32
AF XY:
0.0573
AC XY:
4260
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.0110
Gnomad4 AMR
AF:
0.102
Gnomad4 ASJ
AF:
0.0750
Gnomad4 EAS
AF:
0.0300
Gnomad4 SAS
AF:
0.0731
Gnomad4 FIN
AF:
0.0839
Gnomad4 NFE
AF:
0.0664
Gnomad4 OTH
AF:
0.0673
Alfa
AF:
0.0625
Hom.:
807
Bravo
AF:
0.0514
TwinsUK
AF:
0.0542
AC:
201
ALSPAC
AF:
0.0532
AC:
205
ESP6500AA
AF:
0.00999
AC:
44
ESP6500EA
AF:
0.0633
AC:
544
ExAC
AF:
0.0617
AC:
7495
Asia WGS
AF:
0.0630
AC:
218
AN:
3478
EpiCase
AF:
0.0628
EpiControl
AF:
0.0635

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Sep 19, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33103541) -

Thrombophilia due to activated protein C resistance Benign:2
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Congenital factor V deficiency Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Budd-Chiari syndrome Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Factor V deficiency Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Thrombophilia due to thrombin defect Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.70
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
9.1
DANN
Uncertain
0.98
DEOGEN2
Benign
0.23
T;T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.40
T;T
MetaRNN
Benign
0.0034
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;.
PrimateAI
Benign
0.30
T
PROVEAN
Uncertain
-3.1
D;D
REVEL
Benign
0.017
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.020
D;D
Polyphen
0.068
B;.
Vest4
0.069
MPC
0.11
ClinPred
0.013
T
GERP RS
2.1
Varity_R
0.079
gMVP
0.24

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs6018; hg19: chr1-169511878; COSMIC: COSV63127421; API