chr1-169546488-C-T

Variant names:

• chr1-169546488-C-T
• rs6036
• NM_000130.5:c.1716G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000130.5(F5):​c.1716G>A​(p.Glu572Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,613,998 control chromosomes in the GnomAD database, including 4,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (456 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4497 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.140
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-169546488-C-T is Benign according to our data. Variant chr1-169546488-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 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.1716G>A	p.Glu572Glu	synonymous	Exon 11 of 25	NP_000121.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F5	ENST00000367797.9	TSL:1 MANE Select	c.1716G>A	p.Glu572Glu	synonymous	Exon 11 of 25	ENSP00000356771.3
	F5	ENST00000367796.3	TSL:5	c.1716G>A	p.Glu572Glu	synonymous	Exon 11 of 25	ENSP00000356770.3
	F5	ENST00000904428.1		c.1611+3313G>A		intron	N/A	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9817 AN: 152128 Hom.: 455 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0760

Gnomad EAS AF: 0.0277

Gnomad SAS AF: 0.0853

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0786

Gnomad OTH AF: 0.0751

GnomAD2 exomes AF: 0.0759 AC: 19067 AN: 251374 AF XY: 0.0776

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0990

Gnomad ASJ exome AF: 0.0718

Gnomad EAS exome AF: 0.0289

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0758

Gnomad OTH exome AF: 0.0856

GnomAD4 exome AF: 0.0746 AC: 108995 AN: 1461750 Hom.: 4497 Cov.: 32 AF XY: 0.0753 AC XY: 54761 AN XY: 727200

African (AFR) AF: 0.0108 AC: 360 AN: 33480

American (AMR) AF: 0.100 AC: 4471 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0720 AC: 1881 AN: 26136

East Asian (EAS) AF: 0.0503 AC: 1997 AN: 39698

South Asian (SAS) AF: 0.0850 AC: 7330 AN: 86252

European-Finnish (FIN) AF: 0.112 AC: 5989 AN: 53412

Middle Eastern (MID) AF: 0.0974 AC: 562 AN: 5768

European-Non Finnish (NFE) AF: 0.0737 AC: 81940 AN: 1111886

Other (OTH) AF: 0.0739 AC: 4465 AN: 60396

GnomAD4 genome AF: 0.0645 AC: 9816 AN: 152248 Hom.: 456 Cov.: 32 AF XY: 0.0678 AC XY: 5044 AN XY: 74420

African (AFR) AF: 0.0134 AC: 555 AN: 41562

American (AMR) AF: 0.110 AC: 1688 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0760 AC: 264 AN: 3472

East Asian (EAS) AF: 0.0276 AC: 143 AN: 5184

South Asian (SAS) AF: 0.0855 AC: 412 AN: 4816

European-Finnish (FIN) AF: 0.114 AC: 1209 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0786 AC: 5347 AN: 68008

Other (OTH) AF: 0.0748 AC: 158 AN: 2112

Alfa AF: 0.0737 Hom.: 681

Bravo AF: 0.0597

Asia WGS AF: 0.0650 AC: 225 AN: 3478

EpiCase AF: 0.0736

EpiControl AF: 0.0765

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
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.6
DANN	Benign	0.71
PhyloP100		-0.14
Mutation Taster		=100/0	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: rs6036; hg19: chr1-169515726; COSMIC: COSV63127447;