rs6037

Positions:

• chr1-169544345-G-T

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.1926C>A​(p.Thr642Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0728 in 1,613,708 control chromosomes in the GnomAD database, including 4,834 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 (450 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4384 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.262

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=-0.56).
• BP6: Variant 1-169544345-G-T is Benign according to our data. Variant chr1-169544345-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 255192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169544345-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.262 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.1926C>A	p.Thr642Thr	synonymous_variant	12/25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.1926C>A	p.Thr642Thr	synonymous_variant	12/25	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3	c.1941C>A	p.Thr647Thr	synonymous_variant	12/25	5		ENSP00000356770.3

Frequencies

GnomAD3 genomes AF: 0.0640 AC: 9732 AN: 152024 Hom.: 449 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.0278

Gnomad SAS AF: 0.0823

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0780

Gnomad OTH AF: 0.0742

GnomAD3 exomes AF: 0.0755 AC: 18959 AN: 251172 Hom.: 885 AF XY: 0.0771 AC XY: 10460 AN XY: 135736

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0717

Gnomad EAS exome AF: 0.0290

Gnomad SAS exome AF: 0.0838

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0750

Gnomad OTH exome AF: 0.0843

GnomAD4 exome AF: 0.0737 AC: 107744 AN: 1461566 Hom.: 4384 Cov.: 33 AF XY: 0.0744 AC XY: 54115 AN XY: 727088

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.0720

Gnomad4 EAS exome AF: 0.0504

Gnomad4 SAS exome AF: 0.0835

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.0727

Gnomad4 OTH exome AF: 0.0730

GnomAD4 genome AF: 0.0640 AC: 9731 AN: 152142 Hom.: 450 Cov.: 32 AF XY: 0.0673 AC XY: 5004 AN XY: 74398

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0761

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.0826

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0780

Gnomad4 OTH AF: 0.0739

Alfa AF: 0.0739 Hom.: 962

Bravo AF: 0.0595

Asia WGS AF: 0.0630 AC: 218 AN: 3478

EpiCase AF: 0.0732

EpiControl AF: 0.0756

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 12, 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 12, 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 12, 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	-0.56
CADD	Benign	5.1
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs6037; hg19: chr1-169513583; COSMIC: COSV63126372;