rs13306334

Positions:

• chr1-169540901-G-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.4189C>T​(p.Leu1397Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,612,520 control chromosomes in the GnomAD database, including 10,768 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (1209 hom., cov: 32)
  • Exomes 𝑓: 0.039 (9559 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.417

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=5.7811585E-6).
• BP6: Variant 1-169540901-G-A is Benign according to our data. Variant chr1-169540901-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 293600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.4189C>T	p.Leu1397Phe	missense_variant	13/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.4189C>T	p.Leu1397Phe	missense_variant	13/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.4204C>T	p.Leu1402Phe	missense_variant	13/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.0466 AC: 7078 AN: 152036 Hom.: 1204 Cov.: 32

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0749

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.0819

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00884

Gnomad OTH AF: 0.0450

GnomAD3 exomes AF: 0.0955 AC: 23952 AN: 250932 Hom.: 4626 AF XY: 0.0922 AC XY: 12503 AN XY: 135592

Gnomad AFR exome AF: 0.00548

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.646

Gnomad SAS exome AF: 0.135

Gnomad FIN exome AF: 0.0779

Gnomad NFE exome AF: 0.00977

Gnomad OTH exome AF: 0.0630

GnomAD4 exome AF: 0.0389 AC: 56798 AN: 1460366 Hom.: 9559 Cov.: 34 AF XY: 0.0414 AC XY: 30043 AN XY: 726526

Gnomad4 AFR exome AF: 0.00386

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.0273

Gnomad4 EAS exome AF: 0.613

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.0763

Gnomad4 NFE exome AF: 0.00626

Gnomad4 OTH exome AF: 0.0604

GnomAD4 genome AF: 0.0466 AC: 7087 AN: 152154 Hom.: 1209 Cov.: 32 AF XY: 0.0555 AC XY: 4129 AN XY: 74370

Gnomad4 AFR AF: 0.00604

Gnomad4 AMR AF: 0.0753

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.626

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.0819

Gnomad4 NFE AF: 0.00884

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0355 Hom.: 1926

Bravo AF: 0.0465

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.0898 AC: 10902

Asia WGS AF: 0.356 AC: 1234 AN: 3478

EpiCase AF: 0.00878

EpiControl AF: 0.00759

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

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	- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

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	0.094
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.77
DANN	Benign	0.84
DEOGEN2	Benign	0.034	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.37	T;T
MetaRNN	Benign	0.0000058	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.033
Sift	Benign	0.26	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.012	B;.
Vest4		0.086
MPC		0.093
ClinPred		0.0016	T
GERP RS		1.3
Varity_R		0.029
gMVP		0.25

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: rs13306334; hg19: chr1-169510139; COSMIC: COSV63122946;