1-169559146-G-A

Variant names:

• chr1-169559146-G-A
• rs6023
• NM_000130.5:c.730+7C>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.730+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,613,268 control chromosomes in the GnomAD database, including 4,966 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (343 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4623 hom.)
• Consequence: F5 NM_000130.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004755
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: -0.564
• Publications: 8 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 (BayesDel_noAF=-0.89).
• BP6: Variant 1-169559146-G-A is Benign according to our data. Variant chr1-169559146-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0848 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.730+7C>T		splice_region intron	N/A	NP_000121.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F5	ENST00000367797.9	TSL:1 MANE Select	c.730+7C>T		splice_region intron	N/A	ENSP00000356771.3
	F5	ENST00000367796.3	TSL:5	c.730+7C>T		splice_region intron	N/A	ENSP00000356770.3

Frequencies

GnomAD3 genomes AF: 0.0570 AC: 8672 AN: 152058 Hom.: 342 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0571

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.00771

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0867

Gnomad OTH AF: 0.0693

GnomAD2 exomes AF: 0.0585 AC: 14675 AN: 250954 AF XY: 0.0600

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.0415

Gnomad ASJ exome AF: 0.0927

Gnomad EAS exome AF: 0.00827

Gnomad FIN exome AF: 0.0393

Gnomad NFE exome AF: 0.0855

Gnomad OTH exome AF: 0.0705

GnomAD4 exome AF: 0.0754 AC: 110159 AN: 1461092 Hom.: 4623 Cov.: 32 AF XY: 0.0748 AC XY: 54366 AN XY: 726890

African (AFR) AF: 0.0139 AC: 466 AN: 33450

American (AMR) AF: 0.0448 AC: 2002 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 2467 AN: 26118

East Asian (EAS) AF: 0.0118 AC: 468 AN: 39688

South Asian (SAS) AF: 0.0312 AC: 2693 AN: 86248

European-Finnish (FIN) AF: 0.0427 AC: 2278 AN: 53300

Middle Eastern (MID) AF: 0.0834 AC: 481 AN: 5766

European-Non Finnish (NFE) AF: 0.0855 AC: 95067 AN: 1111430

Other (OTH) AF: 0.0702 AC: 4237 AN: 60378

GnomAD4 genome AF: 0.0570 AC: 8670 AN: 152176 Hom.: 343 Cov.: 32 AF XY: 0.0541 AC XY: 4028 AN XY: 74402

African (AFR) AF: 0.0163 AC: 677 AN: 41530

American (AMR) AF: 0.0571 AC: 872 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 366 AN: 3468

East Asian (EAS) AF: 0.00773 AC: 40 AN: 5176

South Asian (SAS) AF: 0.0299 AC: 144 AN: 4822

European-Finnish (FIN) AF: 0.0372 AC: 394 AN: 10602

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0867 AC: 5890 AN: 67974

Other (OTH) AF: 0.0676 AC: 143 AN: 2114

Alfa AF: 0.0768 Hom.: 809

Bravo AF: 0.0571

Asia WGS AF: 0.0340 AC: 118 AN: 3478

EpiCase AF: 0.0902

EpiControl AF: 0.0934

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.15
DANN	Benign	0.50
PhyloP100		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0040
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: rs6023; hg19: chr1-169528384; COSMIC: COSV63130054;