rs1046712

Variant names:

• chr1-169541237-G-T
• rs1046712
• NM_000130.5:c.3853C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-169541237-G-T
• chr1-169541237-G-A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:9
• Conservation: PhyloP100: -0.143
• Publications: 22 publications found

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]

F5 Gene-Disease associations (from GenCC):

• thrombophilia due to activated protein C resistance

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• congenital factor V deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• East Texas bleeding disorder

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 255205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000130.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F5	NM_000130.5	MANE Select	c.3853C>A	p.Leu1285Ile	missense	Exon 13 of 25	NP_000121.2	P12259

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F5	ENST00000367797.9	TSL:1 MANE Select	c.3853C>A	p.Leu1285Ile	missense	Exon 13 of 25	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.3868C>A	p.Leu1290Ile	missense	Exon 13 of 25	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.1611+8564C>A		intron	N/A	ENSP00000574487.1

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

GnomAD2 exomes AF: 0.174 AC: 43421 AN: 249792 AF XY: 0.177

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 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

African (AFR) AF: 0.173 AC: 5766 AN: 33290

American (AMR) AF: 0.137 AC: 6054 AN: 44048

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6534 AN: 25990

East Asian (EAS) AF: 0.0892 AC: 3526 AN: 39548

South Asian (SAS) AF: 0.199 AC: 16933 AN: 85180

European-Finnish (FIN) AF: 0.204 AC: 10854 AN: 53170

Middle Eastern (MID) AF: 0.158 AC: 910 AN: 5748

European-Non Finnish (NFE) AF: 0.174 AC: 192715 AN: 1109260

Other (OTH) AF: 0.176 AC: 10579 AN: 60130

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

African (AFR) AF: 0.157 AC: 6245 AN: 39850

American (AMR) AF: 0.145 AC: 2158 AN: 14900

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 761 AN: 3380

East Asian (EAS) AF: 0.0915 AC: 459 AN: 5018

South Asian (SAS) AF: 0.184 AC: 843 AN: 4572

European-Finnish (FIN) AF: 0.192 AC: 1923 AN: 10010

Middle Eastern (MID) AF: 0.180 AC: 51 AN: 284

European-Non Finnish (NFE) AF: 0.165 AC: 10959 AN: 66426

Other (OTH) AF: 0.162 AC: 333 AN: 2060

Alfa AF: 0.179 Hom.: 2127

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Thrombophilia due to activated protein C resistance (2)
-	-	1	Budd-Chiari syndrome (1)
-	-	1	Congenital factor V deficiency (1)
-	-	1	Factor V deficiency (1)
-	-	1	not specified (1)
-	-	1	Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.14
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.031
Sift	Benign	0.15	T
Sift4G	Benign	0.29	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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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