NM_000130.5:c.237A>G

Variant names:

• chr1-169582444-T-C
• rs6028
• NM_000130.5:c.237A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000130.5(F5):​c.237A>G​(p.Gln79Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,507,572 control chromosomes in the GnomAD database, including 58,939 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4921 hom., cov: 33)
  • Exomes 𝑓: 0.28 (54018 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.610
• Publications: 38 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-169582444-T-C is Benign according to our data. Variant chr1-169582444-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 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.237A>G	p.Gln79Gln	synonymous	Exon 2 of 25	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.237A>G	p.Gln79Gln	synonymous	Exon 2 of 25	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.237A>G	p.Gln79Gln	synonymous	Exon 2 of 25	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.237A>G	p.Gln79Gln	synonymous	Exon 2 of 21	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35185 AN: 152090 Hom.: 4909 Cov.: 33

Gnomad AFR AF: 0.0677

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.248

GnomAD2 exomes AF: 0.291 AC: 70058 AN: 240928 AF XY: 0.291

Gnomad AFR exome AF: 0.0623

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.191

Gnomad FIN exome AF: 0.343

Gnomad NFE exome AF: 0.280

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.275 AC: 373211 AN: 1355362 Hom.: 54018 Cov.: 22 AF XY: 0.278 AC XY: 188256 AN XY: 678108

African (AFR) AF: 0.0545 AC: 1752 AN: 32174

American (AMR) AF: 0.415 AC: 17554 AN: 42274

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 6452 AN: 25034

East Asian (EAS) AF: 0.255 AC: 9934 AN: 38920

South Asian (SAS) AF: 0.335 AC: 26823 AN: 80186

European-Finnish (FIN) AF: 0.339 AC: 17760 AN: 52338

Middle Eastern (MID) AF: 0.207 AC: 1143 AN: 5532

European-Non Finnish (NFE) AF: 0.271 AC: 277408 AN: 1022328

Other (OTH) AF: 0.254 AC: 14385 AN: 56576

GnomAD4 genome AF: 0.231 AC: 35201 AN: 152210 Hom.: 4921 Cov.: 33 AF XY: 0.237 AC XY: 17667 AN XY: 74400

African (AFR) AF: 0.0675 AC: 2806 AN: 41570

American (AMR) AF: 0.323 AC: 4942 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 913 AN: 3468

East Asian (EAS) AF: 0.219 AC: 1138 AN: 5194

South Asian (SAS) AF: 0.358 AC: 1725 AN: 4824

European-Finnish (FIN) AF: 0.353 AC: 3726 AN: 10560

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19227 AN: 67984

Other (OTH) AF: 0.244 AC: 515 AN: 2114

Alfa AF: 0.261 Hom.: 16624

Bravo AF: 0.223

Asia WGS AF: 0.273 AC: 946 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	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	Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.5
DANN	Benign	0.53
PhyloP100		0.61
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: rs6028; hg19: chr1-169551682; COSMIC: COSV63121541;