rs2239851

Positions:

• chr1-169543259-C-A
• chr1-169543259-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000130.5(F5):​c.1976-145G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 704,150 control chromosomes in the GnomAD database, including 25,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4760 hom., cov: 32)
  • Exomes 𝑓: 0.27 (20827 hom.)
• Consequence: F5 NM_000130.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0260

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-169543259-C-A is Benign according to our data. Variant chr1-169543259-C-A is described in ClinVar as [Benign]. Clinvar id is 1242176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F5	NM_000130.5	c.1976-145G>T		intron_variant		ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.1976-145G>T		intron_variant		1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3	c.1991-145G>T		intron_variant		5		ENSP00000356770.3

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37277 AN: 151936 Hom.: 4748 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.268 AC: 148186 AN: 552098 Hom.: 20827 AF XY: 0.271 AC XY: 79769 AN XY: 294836

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.400

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.228

Gnomad4 SAS exome AF: 0.323

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.266

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.245 AC: 37317 AN: 152052 Hom.: 4760 Cov.: 32 AF XY: 0.247 AC XY: 18364 AN XY: 74312

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.235

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.261

Alfa AF: 0.270 Hom.: 7556

Bravo AF: 0.254

Asia WGS AF: 0.283 AC: 982 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.7
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs2239851; hg19: chr1-169512497; COSMIC: COSV63128779;