rs6018

chr1-169542640-T-G

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.2450A>C(p.Asn817Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0611 in 1,613,968 control chromosomes in the GnomAD database, including 3,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (357 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3182 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.208

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=0.0034109354).
• BP6: Variant 1-169542640-T-G is Benign according to our data. Variant chr1-169542640-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 255199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169542640-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.2450A>C	p.Asn817Thr	missense_variant	13/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.2450A>C	p.Asn817Thr	missense_variant	13/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.2465A>C	p.Asn822Thr	missense_variant	13/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8356 AN: 152026 Hom.: 356 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0750

Gnomad EAS AF: 0.0299

Gnomad SAS AF: 0.0730

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0675

GnomAD3 exomes AF: 0.0654 AC: 16423 AN: 251256 Hom.: 677 AF XY: 0.0662 AC XY: 8983 AN XY: 135790

Gnomad AFR exome AF: 0.00898

Gnomad AMR exome AF: 0.0957

Gnomad ASJ exome AF: 0.0699

Gnomad EAS exome AF: 0.0303

Gnomad SAS exome AF: 0.0741

Gnomad FIN exome AF: 0.0855

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0742

GnomAD4 exome AF: 0.0618 AC: 90317 AN: 1461824 Hom.: 3182 Cov.: 54 AF XY: 0.0626 AC XY: 45535 AN XY: 727210

Gnomad4 AFR exome AF: 0.00908

Gnomad4 AMR exome AF: 0.0962

Gnomad4 ASJ exome AF: 0.0705

Gnomad4 EAS exome AF: 0.0599

Gnomad4 SAS exome AF: 0.0738

Gnomad4 FIN exome AF: 0.0835

Gnomad4 NFE exome AF: 0.0597

Gnomad4 OTH exome AF: 0.0619

GnomAD4 genome AF: 0.0549 AC: 8358 AN: 152144 Hom.: 357 Cov.: 32 AF XY: 0.0573 AC XY: 4260 AN XY: 74380

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.0750

Gnomad4 EAS AF: 0.0300

Gnomad4 SAS AF: 0.0731

Gnomad4 FIN AF: 0.0839

Gnomad4 NFE AF: 0.0664

Gnomad4 OTH AF: 0.0673

Alfa AF: 0.0625 Hom.: 807

Bravo AF: 0.0514

TwinsUK AF: 0.0542 AC: 201

ALSPAC AF: 0.0532 AC: 205

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.0633 AC: 544

ExAC AF: 0.0617 AC: 7495

Asia WGS AF: 0.0630 AC: 218 AN: 3478

EpiCase AF: 0.0628

EpiControl AF: 0.0635

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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	- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 19, 2019

This variant is associated with the following publications: (PMID: 33103541) -

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	0.18
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	9.1
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.017
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.068	B;.
Vest4		0.069
MPC		0.11
ClinPred		0.013	T
GERP RS		2.1
Varity_R		0.079
gMVP		0.24

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: rs6018; hg19: chr1-169511878; COSMIC: COSV63127421;