rs6019

Variant names:

• chr1-169572275-C-G
• rs6019
• NM_000130.5:c.319G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-169572275-C-G
• chr1-169572275-C-T

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.319G>C​(p.Asp107His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 1,612,870 control chromosomes in the GnomAD database, including 7,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2680 hom., cov: 32)
  • Exomes 𝑓: 0.061 (4588 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.813
• Publications: 33 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=0.0040112734).
• BP6: Variant 1-169572275-C-G is Benign according to our data. Variant chr1-169572275-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 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.319G>C	p.Asp107His	missense	Exon 3 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.319G>C	p.Asp107His	missense	Exon 3 of 25	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.319G>C	p.Asp107His	missense	Exon 3 of 25	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.319G>C	p.Asp107His	missense	Exon 3 of 21	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19982 AN: 151980 Hom.: 2676 Cov.: 32

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0683

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0234

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0574

Gnomad OTH AF: 0.0989

GnomAD2 exomes AF: 0.0623 AC: 15617 AN: 250658 AF XY: 0.0554

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.0488

Gnomad ASJ exome AF: 0.0534

Gnomad EAS exome AF: 0.000436

Gnomad FIN exome AF: 0.0255

Gnomad NFE exome AF: 0.0554

Gnomad OTH exome AF: 0.0641

GnomAD4 exome AF: 0.0610 AC: 89113 AN: 1460772 Hom.: 4588 Cov.: 31 AF XY: 0.0585 AC XY: 42500 AN XY: 726700

African (AFR) AF: 0.357 AC: 11931 AN: 33412

American (AMR) AF: 0.0524 AC: 2341 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 1412 AN: 26106

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39666

South Asian (SAS) AF: 0.0128 AC: 1107 AN: 86238

European-Finnish (FIN) AF: 0.0283 AC: 1507 AN: 53186

Middle Eastern (MID) AF: 0.0792 AC: 456 AN: 5760

European-Non Finnish (NFE) AF: 0.0594 AC: 66005 AN: 1111432

Other (OTH) AF: 0.0721 AC: 4347 AN: 60320

GnomAD4 genome AF: 0.131 AC: 19990 AN: 152098 Hom.: 2680 Cov.: 32 AF XY: 0.124 AC XY: 9195 AN XY: 74372

African (AFR) AF: 0.346 AC: 14342 AN: 41428

American (AMR) AF: 0.0681 AC: 1041 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4820

European-Finnish (FIN) AF: 0.0234 AC: 248 AN: 10604

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0574 AC: 3905 AN: 67990

Other (OTH) AF: 0.0979 AC: 207 AN: 2114

Alfa AF: 0.0676 Hom.: 451

Bravo AF: 0.145

TwinsUK AF: 0.0609 AC: 226

ALSPAC AF: 0.0573 AC: 221

ESP6500AA AF: 0.342 AC: 1506

ESP6500EA AF: 0.0548 AC: 471

ExAC AF: 0.0685 AC: 8319

Asia WGS AF: 0.0280 AC: 98 AN: 3478

EpiCase AF: 0.0575

EpiControl AF: 0.0570

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	0.16
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.021
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0040	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.81
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.33
Sift	Benign	0.14	T
Sift4G	Benign	0.13	T
Polyphen		0.063	B
Vest4		0.11
MPC		0.13
ClinPred		0.019	T
GERP RS		3.2
Varity_R		0.16
gMVP		0.62
Mutation Taster		=297/3	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: rs6019; hg19: chr1-169541513; COSMIC: COSV107452967;