rs2239854

Variant names:

• chr1-169556570-G-A
• rs2239854
• NM_000130.5:c.952+76C>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.952+76C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,430,544 control chromosomes in the GnomAD database, including 69,629 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6359 hom., cov: 31)
  • Exomes 𝑓: 0.31 (63270 hom.)
• Consequence: F5 NM_000130.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.900
• Publications: 13 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=-0.91).
• BP6: Variant 1-169556570-G-A is Benign according to our data. Variant chr1-169556570-G-A is described in ClinVar as Benign. ClinVar VariationId is 1247250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5	c.952+76C>T		intron_variant	Intron 6 of 24	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.952+76C>T		intron_variant	Intron 6 of 24	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3	c.952+76C>T		intron_variant	Intron 6 of 24	5		ENSP00000356770.3

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42918 AN: 151864 Hom.: 6341 Cov.: 31

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.287

GnomAD4 exome AF: 0.311 AC: 397370 AN: 1278562 Hom.: 63270 AF XY: 0.311 AC XY: 199732 AN XY: 642026

African (AFR) AF: 0.209 AC: 6216 AN: 29766

American (AMR) AF: 0.436 AC: 17792 AN: 40832

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 6918 AN: 24780

East Asian (EAS) AF: 0.261 AC: 9864 AN: 37790

South Asian (SAS) AF: 0.349 AC: 28029 AN: 80212

European-Finnish (FIN) AF: 0.358 AC: 18301 AN: 51176

Middle Eastern (MID) AF: 0.224 AC: 1204 AN: 5366

European-Non Finnish (NFE) AF: 0.307 AC: 293367 AN: 954184

Other (OTH) AF: 0.288 AC: 15679 AN: 54456

GnomAD4 genome AF: 0.283 AC: 42971 AN: 151982 Hom.: 6359 Cov.: 31 AF XY: 0.288 AC XY: 21369 AN XY: 74272

African (AFR) AF: 0.210 AC: 8715 AN: 41450

American (AMR) AF: 0.352 AC: 5377 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 947 AN: 3470

East Asian (EAS) AF: 0.219 AC: 1134 AN: 5176

South Asian (SAS) AF: 0.360 AC: 1736 AN: 4820

European-Finnish (FIN) AF: 0.370 AC: 3897 AN: 10528

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.299 AC: 20351 AN: 67954

Other (OTH) AF: 0.287 AC: 604 AN: 2106

Alfa AF: 0.295 Hom.: 11244

Bravo AF: 0.280

Asia WGS AF: 0.283 AC: 984 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.1
DANN	Benign	0.60
PhyloP100		0.90
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: rs2239854; hg19: chr1-169525808; COSMIC: COSV63124099;