1-169560735-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000130.5(F5):c.405G>A(p.Ala135=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,612,154 control chromosomes in the GnomAD database, including 45,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8966 hom., cov: 31)
  • Exomes 𝑓: 0.20 (36085 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.79

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 -16 ACMG points.

• BP6: Variant 1-169560735-C-T is Benign according to our data. Variant chr1-169560735-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169560735-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.405G>A	p.Ala135=	synonymous_variant	4/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.405G>A	p.Ala135=	synonymous_variant	4/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.405G>A	p.Ala135=	synonymous_variant	4/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46101 AN: 151608 Hom.: 8956 Cov.: 31

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.0879

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.285

GnomAD3 exomes AF: 0.257 AC: 64502 AN: 251236 Hom.: 11156 AF XY: 0.245 AC XY: 33228 AN XY: 135788

Gnomad AFR exome AF: 0.525

Gnomad AMR exome AF: 0.267

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.679

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.200 AC: 292195 AN: 1460430 Hom.: 36085 Cov.: 35 AF XY: 0.198 AC XY: 143756 AN XY: 726508

Gnomad4 AFR exome AF: 0.530

Gnomad4 AMR exome AF: 0.271

Gnomad4 ASJ exome AF: 0.210

Gnomad4 EAS exome AF: 0.600

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.242

GnomAD4 genome AF: 0.304 AC: 46142 AN: 151724 Hom.: 8966 Cov.: 31 AF XY: 0.306 AC XY: 22699 AN XY: 74120

Gnomad4 AFR AF: 0.518

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.651

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.288

Alfa AF: 0.209 Hom.: 7996

Bravo AF: 0.319

Asia WGS AF: 0.447 AC: 1554 AN: 3478

EpiCase AF: 0.173

EpiControl AF: 0.175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombophilia due to activated protein C resistance Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital factor V deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Budd-Chiari syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Factor V deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Thrombophilia due to thrombin defect Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	17
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6029; hg19: chr1-169529973; COSMIC: COSV63124971;