rs6015

chr1-169550656-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000130.5(F5):c.1380C>T(p.Asn460=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0734 in 1,612,416 control chromosomes in the GnomAD database, including 4,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (459 hom., cov: 31)
  • Exomes 𝑓: 0.074 (4482 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-169550656-G-A is Benign according to our data. Variant chr1-169550656-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169550656-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.1380C>T	p.Asn460=	synonymous_variant	9/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.1380C>T	p.Asn460=	synonymous_variant	9/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.1380C>T	p.Asn460=	synonymous_variant	9/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.0647 AC: 9833 AN: 152078 Hom.: 458 Cov.: 31

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0764

Gnomad EAS AF: 0.0272

Gnomad SAS AF: 0.0831

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0788

Gnomad OTH AF: 0.0757

GnomAD3 exomes AF: 0.0755 AC: 18979 AN: 251288 Hom.: 899 AF XY: 0.0772 AC XY: 10488 AN XY: 135806

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0971

Gnomad ASJ exome AF: 0.0716

Gnomad EAS exome AF: 0.0287

Gnomad SAS exome AF: 0.0835

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0759

Gnomad OTH exome AF: 0.0855

GnomAD4 exome AF: 0.0743 AC: 108484 AN: 1460220 Hom.: 4482 Cov.: 31 AF XY: 0.0750 AC XY: 54470 AN XY: 726534

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.0985

Gnomad4 ASJ exome AF: 0.0718

Gnomad4 EAS exome AF: 0.0504

Gnomad4 SAS exome AF: 0.0826

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.0735

Gnomad4 OTH exome AF: 0.0737

GnomAD4 genome AF: 0.0646 AC: 9831 AN: 152196 Hom.: 459 Cov.: 31 AF XY: 0.0679 AC XY: 5052 AN XY: 74408

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.0764

Gnomad4 EAS AF: 0.0271

Gnomad4 SAS AF: 0.0832

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.0788

Gnomad4 OTH AF: 0.0754

Alfa AF: 0.0754 Hom.: 605

Bravo AF: 0.0597

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.0736

EpiControl AF: 0.0768

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Invitae

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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 19, 2019

- -

Thrombophilia due to thrombin defect 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	8.3
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs6015; hg19: chr1-169519894; COSMIC: COSV63127451;