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GeneBe

rs9332701

chr1-169515529-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000130.5(F5):c.6443T>C(p.Met2148Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0422 in 1,613,552 control chromosomes in the GnomAD database, including 1,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 124 hom., cov: 32)
Exomes 𝑓: 0.043 ( 1687 hom. )

Consequence

F5
NM_000130.5 missense

Scores

4
9
5

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.76
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a disulfide_bond (size 155) in uniprot entity FA5_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000130.5
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.012470007).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-169515529-A-G is Benign according to our data. Variant chr1-169515529-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 255214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169515529-A-G is described in Lovd as [Benign]. Variant chr1-169515529-A-G is described in Lovd as [Likely_benign].
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
F5NM_000130.5 linkuse as main transcriptc.6443T>C p.Met2148Thr missense_variant 24/25 ENST00000367797.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
F5ENST00000367797.9 linkuse as main transcriptc.6443T>C p.Met2148Thr missense_variant 24/251 NM_000130.5 P2
F5ENST00000367796.3 linkuse as main transcriptc.6458T>C p.Met2153Thr missense_variant 24/255 A2
F5ENST00000495481.1 linkuse as main transcriptn.217T>C non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0305
AC:
4632
AN:
152044
Hom.:
124
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00858
Gnomad AMI
AF:
0.0428
Gnomad AMR
AF:
0.0147
Gnomad ASJ
AF:
0.0181
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0139
Gnomad FIN
AF:
0.0392
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0504
Gnomad OTH
AF:
0.0215
GnomAD3 exomes
AF:
0.0303
AC:
7611
AN:
251034
Hom.:
163
AF XY:
0.0308
AC XY:
4174
AN XY:
135646
show subpopulations
Gnomad AFR exome
AF:
0.00806
Gnomad AMR exome
AF:
0.0128
Gnomad ASJ exome
AF:
0.0191
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0142
Gnomad FIN exome
AF:
0.0409
Gnomad NFE exome
AF:
0.0471
Gnomad OTH exome
AF:
0.0299
GnomAD4 exome
AF:
0.0434
AC:
63460
AN:
1461390
Hom.:
1687
Cov.:
32
AF XY:
0.0427
AC XY:
31062
AN XY:
727012
show subpopulations
Gnomad4 AFR exome
AF:
0.00670
Gnomad4 AMR exome
AF:
0.0128
Gnomad4 ASJ exome
AF:
0.0188
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0149
Gnomad4 FIN exome
AF:
0.0418
Gnomad4 NFE exome
AF:
0.0506
Gnomad4 OTH exome
AF:
0.0394
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0304
AC:
4630
AN:
152162
Hom.:
124
Cov.:
32
AF XY:
0.0281
AC XY:
2091
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.00855
Gnomad4 AMR
AF:
0.0146
Gnomad4 ASJ
AF:
0.0181
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0139
Gnomad4 FIN
AF:
0.0392
Gnomad4 NFE
AF:
0.0504
Gnomad4 OTH
AF:
0.0213
Alfa
AF:
0.0397
Hom.:
174
Bravo
AF:
0.0278
TwinsUK
AF:
0.0537
AC:
199
ALSPAC
AF:
0.0503
AC:
194
ESP6500AA
AF:
0.0104
AC:
46
ESP6500EA
AF:
0.0447
AC:
384
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0305
AC:
3707
Asia WGS
AF:
0.00549
AC:
19
AN:
3478
EpiCase
AF:
0.0400
EpiControl
AF:
0.0435

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 28, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Thrombophilia due to activated protein C resistance Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Congenital factor V deficiency Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Budd-Chiari syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
Pathogenic
0.68
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Uncertain
-0.030
Cadd
Uncertain
25
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.57
D;T
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.83
T;T
MetaRNN
Benign
0.012
T;T
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.8
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-4.8
D;D
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.012
D;D
Polyphen
1.0
D;.
Vest4
0.45
MPC
0.50
ClinPred
0.022
T
GERP RS
5.6
Varity_R
0.78
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs9332701; hg19: chr1-169484767; API