1-169549874-C-T

Position:

• chr1-169549874-C-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.1538G>A​(p.Arg513Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0539 in 1,613,922 control chromosomes in the GnomAD database, including 14,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2984 hom., cov: 32)
  • Exomes 𝑓: 0.047 (11733 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.10

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=7.3489547E-4).
• BP6: Variant 1-169549874-C-T is Benign according to our data. Variant chr1-169549874-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 293628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F5	NM_000130.5	c.1538G>A	p.Arg513Lys	missense_variant	10/25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.1538G>A	p.Arg513Lys	missense_variant	10/25	1	NM_000130.5	ENSP00000356771	P2
F5	ENST00000367796.3	c.1538G>A	p.Arg513Lys	missense_variant	10/25	5		ENSP00000356770	A2

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18830 AN: 152018 Hom.: 2980 Cov.: 32

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0820

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.0586

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.111 AC: 27918 AN: 251418 Hom.: 5229 AF XY: 0.103 AC XY: 13934 AN XY: 135880

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.0610

Gnomad EAS exome AF: 0.652

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.0545

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0693

GnomAD4 exome AF: 0.0466 AC: 68142 AN: 1461784 Hom.: 11733 Cov.: 32 AF XY: 0.0478 AC XY: 34737 AN XY: 727194

Gnomad4 AFR exome AF: 0.290

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.0568

Gnomad4 EAS exome AF: 0.650

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.0521

Gnomad4 NFE exome AF: 0.00668

Gnomad4 OTH exome AF: 0.0799

GnomAD4 genome AF: 0.124 AC: 18859 AN: 152138 Hom.: 2984 Cov.: 32 AF XY: 0.130 AC XY: 9668 AN XY: 74386

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.0823

Gnomad4 ASJ AF: 0.0689

Gnomad4 EAS AF: 0.643

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0586

Gnomad4 NFE AF: 0.00919

Gnomad4 OTH AF: 0.111

Alfa AF: 0.0454 Hom.: 2644

Bravo AF: 0.136

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.268 AC: 1183

ESP6500EA AF: 0.0108 AC: 93

ExAC AF: 0.112 AC: 13593

Asia WGS AF: 0.375 AC: 1302 AN: 3478

EpiCase AF: 0.0108

EpiControl AF: 0.0104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 32211132, 11950065, 10845571, 9798997, 23662219) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Mar 06, 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

Mar 06, 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 activated protein C resistance Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Thrombophilia due to thrombin defect Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.00073	T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.92	L;.
MutationTaster	Benign	0.21	P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.44
Sift	Benign	0.25	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.91	P;.
Vest4		0.19
MPC		0.47
ClinPred		0.018	T
GERP RS		5.7
Varity_R		0.21
gMVP		0.94

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: rs6020; hg19: chr1-169519112; COSMIC: COSV63123547;