rs12755775

Variant names:

• chr1-169578479-G-A
• rs12755775
• NM_000130.5:c.250+3952C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000130.5(F5):​c.250+3952C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 152,132 control chromosomes in the GnomAD database, including 585 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.075 (585 hom., cov: 31)
• Consequence: F5 NM_000130.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.65
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5	c.250+3952C>T		intron_variant	Intron 2 of 24	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.250+3952C>T		intron_variant	Intron 2 of 24	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3	c.250+3952C>T		intron_variant	Intron 2 of 24	5		ENSP00000356770.3

Frequencies

GnomAD3 genomes AF: 0.0749 AC: 11384 AN: 152014 Hom.: 585 Cov.: 31

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0827

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0705

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0861

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0748 AC: 11386 AN: 152132 Hom.: 585 Cov.: 31 AF XY: 0.0719 AC XY: 5348 AN XY: 74352

African (AFR) AF: 0.0313 AC: 1300 AN: 41508

American (AMR) AF: 0.0825 AC: 1261 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 134 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4816

European-Finnish (FIN) AF: 0.0705 AC: 744 AN: 10558

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7561 AN: 68004

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0845 Hom.: 526

Bravo AF: 0.0734

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.084
DANN	Benign	0.52
PhyloP100		-2.6
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: rs12755775; hg19: chr1-169547717; COSMIC: COSV63125850;