rs6035

chr1-169552611-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000130.5(F5):c.1242A>G(p.Lys414=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0839 in 1,613,148 control chromosomes in the GnomAD database, including 5,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (606 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5275 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.122

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-169552611-T-C is Benign according to our data. Variant chr1-169552611-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.122 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.1242A>G	p.Lys414=	synonymous_variant	8/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.1242A>G	p.Lys414=	synonymous_variant	8/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.1242A>G	p.Lys414=	synonymous_variant	8/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.0863 AC: 13124 AN: 152140 Hom.: 607 Cov.: 32

Gnomad AFR AF: 0.0945

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0955

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.0604

Gnomad SAS AF: 0.0942

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0817

Gnomad OTH AF: 0.0900

GnomAD3 exomes AF: 0.0877 AC: 22041 AN: 251372 Hom.: 1034 AF XY: 0.0875 AC XY: 11886 AN XY: 135850

Gnomad AFR exome AF: 0.0939

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.0636

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.0576

Gnomad NFE exome AF: 0.0826

Gnomad OTH exome AF: 0.0856

GnomAD4 exome AF: 0.0836 AC: 122170 AN: 1460890 Hom.: 5275 Cov.: 31 AF XY: 0.0844 AC XY: 61319 AN XY: 726772

Gnomad4 AFR exome AF: 0.0945

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.0595

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.0581

Gnomad4 NFE exome AF: 0.0815

Gnomad4 OTH exome AF: 0.0882

GnomAD4 genome AF: 0.0862 AC: 13127 AN: 152258 Hom.: 606 Cov.: 32 AF XY: 0.0837 AC XY: 6235 AN XY: 74458

Gnomad4 AFR AF: 0.0944

Gnomad4 AMR AF: 0.0952

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.0607

Gnomad4 SAS AF: 0.0939

Gnomad4 FIN AF: 0.0573

Gnomad4 NFE AF: 0.0817

Gnomad4 OTH AF: 0.0914

Alfa AF: 0.0896 Hom.: 795

Bravo AF: 0.0877

Asia WGS AF: 0.103 AC: 358 AN: 3476

EpiCase AF: 0.0922

EpiControl AF: 0.0906

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 27884173, 16542711, 20981092) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -

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

- -

Thrombophilia due to activated protein C resistance Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	5.4
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs6035; hg19: chr1-169521849; COSMIC: COSV63123986;