rs1046712

chr1-169541237-G-T

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.3853C>A(p.Leu1285Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,603,754 control chromosomes in the GnomAD database, including 24,165 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1350 hom., cov: 26)
  • Exomes 𝑓: 0.17 (22815 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: -0.143

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=0.0068129003).
• BP6: Variant 1-169541237-G-T is Benign according to our data. Variant chr1-169541237-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 255205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169541237-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.3853C>A	p.Leu1285Ile	missense_variant	13/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.3853C>A	p.Leu1285Ile	missense_variant	13/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.3868C>A	p.Leu1290Ile	missense_variant	13/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 23833 AN: 147284 Hom.: 1353 Cov.: 26

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.0917

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.174 AC: 43421 AN: 249792 Hom.: 3963 AF XY: 0.177 AC XY: 23922 AN XY: 135034

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.0957

Gnomad SAS exome AF: 0.201

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.174 AC: 253871 AN: 1456364 Hom.: 22815 Cov.: 129 AF XY: 0.175 AC XY: 127054 AN XY: 724344

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.251

Gnomad4 EAS exome AF: 0.0892

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.162 AC: 23841 AN: 147390 Hom.: 1350 Cov.: 26 AF XY: 0.162 AC XY: 11665 AN XY: 71960

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.0915

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.162

Alfa AF: 0.178 Hom.: 1466

TwinsUK AF: 0.183 AC: 677

ALSPAC AF: 0.173 AC: 667

ESP6500AA AF: 0.176 AC: 775

ESP6500EA AF: 0.175 AC: 1502

ExAC AF: 0.179 AC: 21699

Asia WGS AF: 0.154 AC: 535 AN: 3462

EpiCase AF: 0.183

EpiControl AF: 0.183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:1

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: 25.185% 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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

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 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
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.20
Dann	Benign	0.16
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.031
Sift	Benign	0.15	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0030	B;.
Vest4		0.083
MPC		0.22
ClinPred		0.0053	T
GERP RS		-1.4
Varity_R		0.024
gMVP		0.19

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: rs1046712; hg19: chr1-169510475; COSMIC: COSV63123971;