rs41272455

Variant names:

• chr1-169529762-T-C
• rs41272455
• NM_000130.5:c.5265A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_000130.5(F5):​c.5265A>G​(p.Ile1755Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,788 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:1
• Conservation: PhyloP100: -0.538
• Publications: 5 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011879802).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00107 (163/152312) while in subpopulation AMR AF = 0.00157 (24/15292). AF 95% confidence interval is 0.00121. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.5265A>G	p.Ile1755Met	missense	Exon 16 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.5265A>G	p.Ile1755Met	missense	Exon 16 of 25	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.5280A>G	p.Ile1760Met	missense	Exon 16 of 25	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.1905A>G	p.Ile635Met	missense	Exon 12 of 21	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000973 AC: 244 AN: 250804 AF XY: 0.000885

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00106 AC: 1556 AN: 1461476 Hom.: 1 Cov.: 33 AF XY: 0.00101 AC XY: 734 AN XY: 727032

African (AFR) AF: 0.000209 AC: 7 AN: 33440

American (AMR) AF: 0.000559 AC: 25 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 95 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.000899 AC: 48 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00119 AC: 1319 AN: 1111748

Other (OTH) AF: 0.00101 AC: 61 AN: 60374

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74476

African (AFR) AF: 0.000361 AC: 15 AN: 41574

American (AMR) AF: 0.00157 AC: 24 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.000869

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000931 AC: 113

EpiCase AF: 0.00104

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Budd-Chiari syndrome (1)
-	1	-	Budd-Chiari syndrome;C0948008:Ischemic stroke;C1861171:Thrombophilia due to activated protein C resistance;C3280670:Pregnancy loss, recurrent, susceptibility to, 1;C4317320:Factor V deficiency (1)
-	-	1	Congenital factor V deficiency (1)
-	1	-	F5-related disorder (1)
-	1	-	Factor V deficiency (1)
-	1	-	Hemorrhage (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Thrombophilia due to activated protein C resistance (1)
-	1	-	Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	1.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.54
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.30
Sift	Benign	0.050	D
Sift4G	Benign	0.068	T
Polyphen		0.052	B
Vest4		0.10
MVP		0.67
MPC		0.10
ClinPred		0.015	T
GERP RS		3.1
Varity_R		0.051
gMVP		0.67
Mutation Taster		=91/9	polymorphism

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: rs41272455; hg19: chr1-169499000; COSMIC: COSV106510681;