rs6023

Positions:

Variant summary

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

The NM_000130.5(F5):c.730+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,613,268 control chromosomes in the GnomAD database, including 4,966 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.057 ( 343 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4623 hom. )

Consequence

F5
NM_000130.5 splice_region, intron

Scores

Splicing: ADA: 0.00004755

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: -0.564

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 (BayesDel_noAF=-0.89).

BP6

Variant 1-169559146-G-A is Benign according to our data. Variant chr1-169559146-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169559146-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F5	NM_000130.5 linkuse as main transcript	c.730+7C>T		splice_region_variant, intron_variant		ENST00000367797.9	NP_000121.2	P12259

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9 linkuse as main transcript	c.730+7C>T		splice_region_variant, intron_variant		1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 linkuse as main transcript	c.730+7C>T		splice_region_variant, intron_variant		5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.0570

AC:

8672

AN:

152058

Hom.:

342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.121

Gnomad AMR

AF:

0.0571

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.00771

Gnomad SAS

AF:

0.0296

Gnomad FIN

AF:

0.0372

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0867

Gnomad OTH

AF:

0.0693

GnomAD3 exomes

AF:

0.0585

AC:

14675

AN:

250954

Hom.:

587

AF XY:

0.0600

AC XY:

8144

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.0150

Gnomad AMR exome

AF:

0.0415

Gnomad ASJ exome

AF:

0.0927

Gnomad EAS exome

AF:

0.00827

Gnomad SAS exome

AF:

0.0307

Gnomad FIN exome

AF:

0.0393

Gnomad NFE exome

AF:

0.0855

Gnomad OTH exome

AF:

0.0705

GnomAD4 exome

AF:

0.0754

AC:

110159

AN:

1461092

Hom.:

4623

Cov.:

AF XY:

0.0748

AC XY:

54366

AN XY:

726890

show subpopulations

Gnomad4 AFR exome

AF:

0.0139

Gnomad4 AMR exome

AF:

0.0448

Gnomad4 ASJ exome

AF:

0.0945

Gnomad4 EAS exome

AF:

0.0118

Gnomad4 SAS exome

AF:

0.0312

Gnomad4 FIN exome

AF:

0.0427

Gnomad4 NFE exome

AF:

0.0855

Gnomad4 OTH exome

AF:

0.0702

GnomAD4 genome

AF:

0.0570

AC:

8670

AN:

152176

Hom.:

343

Cov.:

AF XY:

0.0541

AC XY:

4028

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0163

Gnomad4 AMR

AF:

0.0571

Gnomad4 ASJ

AF:

0.106

Gnomad4 EAS

AF:

0.00773

Gnomad4 SAS

AF:

0.0299

Gnomad4 FIN

AF:

0.0372

Gnomad4 NFE

AF:

0.0867

Gnomad4 OTH

AF:

0.0676

Alfa

AF:

0.0787

Hom.:

699

Bravo

AF:

0.0571

Asia WGS

AF:

0.0340

AC:

118

AN:

3478

EpiCase

AF:

0.0902

EpiControl

AF:

0.0934

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 9.27% in gnomAD_ExomesFounderPop) based on the frequency threshold of 5.0% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease. -

Thrombophilia due to activated protein C resistance

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Congenital factor V deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Budd-Chiari syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Factor V deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Thrombophilia due to thrombin defect

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.15

DANN

Benign

0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000048

dbscSNV1_RF

Benign

0.0040

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