rs6036

Positions:

• chr1-169546488-C-T

Variant summary

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

The ENST00000367797.9(F5):​c.1716G>A​(p.Glu572=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,613,998 control chromosomes in the GnomAD database, including 4,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (456 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4497 hom.)
• Consequence: F5 ENST00000367797.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.140

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=-0.54).
• BP6: Variant 1-169546488-C-T is Benign according to our data. Variant chr1-169546488-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169546488-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.14 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	Protein	UniProt
F5	NM_000130.5	c.1716G>A	p.Glu572=	synonymous_variant	11/25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.1716G>A	p.Glu572=	synonymous_variant	11/25	1	NM_000130.5	ENSP00000356771	P2
F5	ENST00000367796.3	c.1716G>A	p.Glu572=	synonymous_variant	11/25	5		ENSP00000356770	A2

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9817 AN: 152128 Hom.: 455 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0760

Gnomad EAS AF: 0.0277

Gnomad SAS AF: 0.0853

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0786

Gnomad OTH AF: 0.0751

GnomAD3 exomes AF: 0.0759 AC: 19067 AN: 251374 Hom.: 909 AF XY: 0.0776 AC XY: 10543 AN XY: 135864

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0990

Gnomad ASJ exome AF: 0.0718

Gnomad EAS exome AF: 0.0289

Gnomad SAS exome AF: 0.0854

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0758

Gnomad OTH exome AF: 0.0856

GnomAD4 exome AF: 0.0746 AC: 108995 AN: 1461750 Hom.: 4497 Cov.: 32 AF XY: 0.0753 AC XY: 54761 AN XY: 727200

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.0720

Gnomad4 EAS exome AF: 0.0503

Gnomad4 SAS exome AF: 0.0850

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.0737

Gnomad4 OTH exome AF: 0.0739

GnomAD4 genome AF: 0.0645 AC: 9816 AN: 152248 Hom.: 456 Cov.: 32 AF XY: 0.0678 AC XY: 5044 AN XY: 74420

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0760

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.0855

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0786

Gnomad4 OTH AF: 0.0748

Alfa AF: 0.0748 Hom.: 565

Bravo AF: 0.0597

Asia WGS AF: 0.0650 AC: 225 AN: 3478

EpiCase AF: 0.0736

EpiControl AF: 0.0765

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

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

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

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	-0.54
CADD	Benign	7.6
DANN	Benign	0.71

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

Other links and lift over

dbSNP: rs6036; hg19: chr1-169515726; COSMIC: COSV63127447;