1-169542347-T-A

Position:

chr1-169542347-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000130.5(F5):c.2743A>T(p.Thr915Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,600,770 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 28 hom., cov: 32)

Exomes 𝑓: 0.015 ( 211 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.125

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]

F5 links:

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=0.0025451481).

BP6

Variant 1-169542347-T-A is Benign according to our data. Variant chr1-169542347-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 293619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0129 (1965/152168) while in subpopulation NFE AF= 0.0159 (1079/67974). AF 95% confidence interval is 0.0151. There are 28 homozygotes in gnomad4. There are 1014 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5 linkuse as main transcript	c.2743A>T	p.Thr915Ser	missense_variant	13/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9 linkuse as main transcript	c.2743A>T	p.Thr915Ser	missense_variant	13/25	1	NM_000130.5	P2
F5	ENST00000367796.3 linkuse as main transcript	c.2758A>T	p.Thr920Ser	missense_variant	13/25	5		A2

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1966

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.0879

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00436

Gnomad FIN

AF:

0.0381

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.0136

AC:

3405

AN:

250998

Hom.:

AF XY:

0.0138

AC XY:

1874

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00787

Gnomad ASJ exome

AF:

0.0259

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00379

Gnomad FIN exome

AF:

0.0398

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0159

GnomAD4 exome

AF:

0.0150

AC:

21724

AN:

1448602

Hom.:

211

Cov.:

AF XY:

0.0146

AC XY:

10509

AN XY:

720696

show subpopulations

Gnomad4 AFR exome

AF:

0.00234

Gnomad4 AMR exome

AF:

0.00876

Gnomad4 ASJ exome

AF:

0.0275

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00346

Gnomad4 FIN exome

AF:

0.0344

Gnomad4 NFE exome

AF:

0.0159

Gnomad4 OTH exome

AF:

0.0149

GnomAD4 genome

AF:

0.0129

AC:

1965

AN:

152168

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1014

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00274

Gnomad4 AMR

AF:

0.00981

Gnomad4 ASJ

AF:

0.0285

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.0381

Gnomad4 NFE

AF:

0.0159

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.0143

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.0181

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0170

AC:

146

ExAC

AF:

0.0129

AC:

1560

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0152

EpiControl

AF:

0.0149

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital factor V deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Budd-Chiari syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Factor V deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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 activated protein C resistance

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Thrombophilia due to thrombin defect

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.70

DANN

Benign

0.094

DEOGEN2

Benign

0.015

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

0.070

N;N

REVEL

Benign

0.034

Sift

Benign

0.76

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.057

MutPred

0.076

Gain of glycosylation at T915 (P = 0.0235);.;

MPC

0.22

ClinPred

0.00042

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.099

gMVP

0.17

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over