NM_000130.5:c.5419+12A>G

Variant names:

• chr1-169529596-T-C
• rs6009
• NM_000130.5:c.5419+12A>G

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.5419+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.936 in 1,610,466 control chromosomes in the GnomAD database, including 705,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65297 hom., cov: 31)
  • Exomes 𝑓: 0.94 (640628 hom.)
• Consequence: F5 NM_000130.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.348
• Publications: 18 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 (BayesDel_noAF=-0.68).
• BP6: Variant 1-169529596-T-C is Benign according to our data. Variant chr1-169529596-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.5419+12A>G		intron	N/A	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.5419+12A>G		intron	N/A	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.5434+12A>G		intron	N/A	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.2059+12A>G		intron	N/A	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.926 AC: 140819 AN: 152078 Hom.: 65245 Cov.: 31

Gnomad AFR AF: 0.895

Gnomad AMI AF: 0.893

Gnomad AMR AF: 0.950

Gnomad ASJ AF: 0.876

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.934

Gnomad FIN AF: 0.950

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.933

Gnomad OTH AF: 0.925

GnomAD2 exomes AF: 0.937 AC: 234759 AN: 250570 AF XY: 0.935

Gnomad AFR exome AF: 0.895

Gnomad AMR exome AF: 0.968

Gnomad ASJ exome AF: 0.881

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.949

Gnomad NFE exome AF: 0.928

Gnomad OTH exome AF: 0.937

GnomAD4 exome AF: 0.937 AC: 1366487 AN: 1458270 Hom.: 640628 Cov.: 33 AF XY: 0.936 AC XY: 679390 AN XY: 725644

African (AFR) AF: 0.895 AC: 29841 AN: 33352

American (AMR) AF: 0.966 AC: 43114 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 23033 AN: 26100

East Asian (EAS) AF: 1.00 AC: 39609 AN: 39624

South Asian (SAS) AF: 0.926 AC: 79839 AN: 86176

European-Finnish (FIN) AF: 0.949 AC: 50611 AN: 53354

Middle Eastern (MID) AF: 0.870 AC: 5008 AN: 5754

European-Non Finnish (NFE) AF: 0.937 AC: 1039211 AN: 1109008

Other (OTH) AF: 0.933 AC: 56221 AN: 60252

GnomAD4 genome AF: 0.926 AC: 140928 AN: 152196 Hom.: 65297 Cov.: 31 AF XY: 0.928 AC XY: 69010 AN XY: 74400

African (AFR) AF: 0.894 AC: 37120 AN: 41500

American (AMR) AF: 0.950 AC: 14517 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.876 AC: 3038 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5189 AN: 5192

South Asian (SAS) AF: 0.934 AC: 4505 AN: 4822

European-Finnish (FIN) AF: 0.950 AC: 10073 AN: 10600

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.933 AC: 63467 AN: 68012

Other (OTH) AF: 0.926 AC: 1955 AN: 2112

Alfa AF: 0.912 Hom.: 18144

Bravo AF: 0.924

Asia WGS AF: 0.970 AC: 3373 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (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 provided (1)
-	-	1	Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.74
PhyloP100		0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs6009; hg19: chr1-169498834;