rs9332485

Variant names:

• chr1-169586344-C-T
• rs9332485
• NM_000130.5:c.43G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000130.5(F5):​c.43G>A​(p.Gly15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,613,982 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (80 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (79 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.228

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002523303).
• BP6: Variant 1-169586344-C-T is Benign according to our data. Variant chr1-169586344-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 293644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5	c.43G>A	p.Gly15Ser	missense_variant	Exon 1 of 25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.43G>A	p.Gly15Ser	missense_variant	Exon 1 of 25	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3	c.43G>A	p.Gly15Ser	missense_variant	Exon 1 of 25	5		ENSP00000356770.3

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2618 AN: 152142 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00472 AC: 1184 AN: 250972 Hom.: 29 AF XY: 0.00340 AC XY: 462 AN XY: 135726

Gnomad AFR exome AF: 0.0598

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00196 AC: 2863 AN: 1461722 Hom.: 79 Cov.: 31 AF XY: 0.00175 AC XY: 1271 AN XY: 727170

Gnomad4 AFR exome AF: 0.0639

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00482

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.000525

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.0172 AC: 2623 AN: 152260 Hom.: 80 Cov.: 32 AF XY: 0.0171 AC XY: 1273 AN XY: 74448

Gnomad4 AFR AF: 0.0587

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0315 Hom.: 3214

Bravo AF: 0.0199

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0524 AC: 231

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00579 AC: 703

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombophilia due to activated protein C resistance Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital factor V deficiency Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Budd-Chiari syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Thrombophilia due to thrombin defect Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.12	T;T
Polyphen		1.0	D;.
Vest4		0.15
MVP		0.92
MPC		0.22
ClinPred		0.033	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.042
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9332485; hg19: chr1-169555582;