rs6033

Variant names:

• chr1-169552615-A-G
• rs6033
• NM_000130.5:c.1238T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-169552615-A-G
• chr1-169552615-A-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.1238T>C​(p.Met413Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,613,272 control chromosomes in the GnomAD database, including 4,955 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (452 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4503 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.506
• Publications: 36 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=0.0017207563).
• BP6: Variant 1-169552615-A-G is Benign according to our data. Variant chr1-169552615-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F5	NM_000130.5	MANE Select	c.1238T>C	p.Met413Thr	missense	Exon 8 of 25	NP_000121.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F5	ENST00000367797.9	TSL:1 MANE Select	c.1238T>C	p.Met413Thr	missense	Exon 8 of 25	ENSP00000356771.3
	F5	ENST00000367796.3	TSL:5	c.1238T>C	p.Met413Thr	missense	Exon 8 of 25	ENSP00000356770.3

Frequencies

GnomAD3 genomes AF: 0.0644 AC: 9787 AN: 152024 Hom.: 451 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0763

Gnomad EAS AF: 0.0277

Gnomad SAS AF: 0.0825

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0788

Gnomad OTH AF: 0.0736

GnomAD2 exomes AF: 0.0756 AC: 19001 AN: 251378 AF XY: 0.0772

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0970

Gnomad ASJ exome AF: 0.0719

Gnomad EAS exome AF: 0.0294

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0760

Gnomad OTH exome AF: 0.0855

GnomAD4 exome AF: 0.0746 AC: 108957 AN: 1461130 Hom.: 4503 Cov.: 31 AF XY: 0.0752 AC XY: 54699 AN XY: 726928

African (AFR) AF: 0.0108 AC: 361 AN: 33464

American (AMR) AF: 0.0981 AC: 4386 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0720 AC: 1882 AN: 26124

East Asian (EAS) AF: 0.0509 AC: 2018 AN: 39626

South Asian (SAS) AF: 0.0825 AC: 7115 AN: 86234

European-Finnish (FIN) AF: 0.114 AC: 6070 AN: 53412

Middle Eastern (MID) AF: 0.0971 AC: 555 AN: 5716

European-Non Finnish (NFE) AF: 0.0739 AC: 82119 AN: 1111480

Other (OTH) AF: 0.0738 AC: 4451 AN: 60352

GnomAD4 genome AF: 0.0643 AC: 9785 AN: 152142 Hom.: 452 Cov.: 32 AF XY: 0.0676 AC XY: 5030 AN XY: 74398

African (AFR) AF: 0.0132 AC: 546 AN: 41518

American (AMR) AF: 0.108 AC: 1651 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0763 AC: 264 AN: 3462

East Asian (EAS) AF: 0.0276 AC: 143 AN: 5180

South Asian (SAS) AF: 0.0826 AC: 398 AN: 4820

European-Finnish (FIN) AF: 0.116 AC: 1229 AN: 10576

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0788 AC: 5359 AN: 67982

Other (OTH) AF: 0.0733 AC: 155 AN: 2114

Alfa AF: 0.0716 Hom.: 1413

Bravo AF: 0.0590

TwinsUK AF: 0.0707 AC: 262

ALSPAC AF: 0.0701 AC: 270

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0784 AC: 674

ExAC AF: 0.0718 AC: 8718

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.0738

EpiControl AF: 0.0769

ClinVar

ClinVar submissions as Germline

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	0.084
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.017
DANN	Benign	0.55
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0017	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	0.14	N
PhyloP100		-0.51
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.22
Sift	Benign	0.65	T
Sift4G	Benign	0.56	T
Polyphen		0.0090	B
Vest4		0.045
MPC		0.10
ClinPred		0.011	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.41
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6033; hg19: chr1-169521853; COSMIC: COSV63126378;