rs2239851

Variant names:

• chr1-169543259-C-A
• rs2239851
• NM_000130.5:c.1976-145G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-169543259-C-A
• chr1-169543259-C-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.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
• Publications: 11 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=-0.85).
• BP6: Variant 1-169543259-C-A is Benign according to our data. Variant chr1-169543259-C-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
F5	NM_000130.5	c.1976-145G>T		intron_variant	Intron 12 of 24	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.1976-145G>T		intron_variant	Intron 12 of 24	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3	c.1991-145G>T		intron_variant	Intron 12 of 24	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

African (AFR) AF: 0.180 AC: 2618 AN: 14532

American (AMR) AF: 0.400 AC: 11437 AN: 28602

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 3156 AN: 17994

East Asian (EAS) AF: 0.228 AC: 7309 AN: 32040

South Asian (SAS) AF: 0.323 AC: 18195 AN: 56330

European-Finnish (FIN) AF: 0.219 AC: 7271 AN: 33140

Middle Eastern (MID) AF: 0.275 AC: 1031 AN: 3750

European-Non Finnish (NFE) AF: 0.266 AC: 89290 AN: 335798

Other (OTH) AF: 0.263 AC: 7879 AN: 29912

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

African (AFR) AF: 0.183 AC: 7600 AN: 41498

American (AMR) AF: 0.342 AC: 5220 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 583 AN: 3464

East Asian (EAS) AF: 0.235 AC: 1217 AN: 5178

South Asian (SAS) AF: 0.324 AC: 1562 AN: 4824

European-Finnish (FIN) AF: 0.211 AC: 2231 AN: 10558

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18111 AN: 67946

Other (OTH) AF: 0.261 AC: 550 AN: 2110

Alfa AF: 0.268 Hom.: 10180

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

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.7
DANN	Benign	0.70
PhyloP100		0.026
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: rs2239851; hg19: chr1-169512497; COSMIC: COSV63128779;