rs6030

chr1-169529737-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000130.5(F5):c.5290A>G(p.Met1764Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,296 control chromosomes in the GnomAD database, including 89,570 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.30 (7249 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82321 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -2.27

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3938546E-4).
• BP6: Variant 1-169529737-T-C is Benign according to our data. Variant chr1-169529737-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255210.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=1}. Variant chr1-169529737-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.5290A>G	p.Met1764Val	missense_variant	16/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.5290A>G	p.Met1764Val	missense_variant	16/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.5305A>G	p.Met1769Val	missense_variant	16/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45508 AN: 151956 Hom.: 7240 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.330

GnomAD3 exomes AF: 0.343 AC: 86072 AN: 250926 Hom.: 15869 AF XY: 0.344 AC XY: 46576 AN XY: 135588

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.258

Gnomad SAS exome AF: 0.406

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.328

Gnomad OTH exome AF: 0.353

GnomAD4 exome AF: 0.332 AC: 485070 AN: 1461222 Hom.: 82321 Cov.: 37 AF XY: 0.334 AC XY: 242557 AN XY: 726920

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.504

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.297

Gnomad4 SAS exome AF: 0.402

Gnomad4 FIN exome AF: 0.296

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.322

GnomAD4 genome AF: 0.299 AC: 45534 AN: 152074 Hom.: 7249 Cov.: 32 AF XY: 0.304 AC XY: 22571 AN XY: 74338

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.441

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.270

Gnomad4 SAS AF: 0.401

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.327

Alfa AF: 0.327 Hom.: 20077

Bravo AF: 0.305

TwinsUK AF: 0.322 AC: 1193

ALSPAC AF: 0.333 AC: 1285

ESP6500AA AF: 0.199 AC: 878

ESP6500EA AF: 0.336 AC: 2886

ExAC AF: 0.335 AC: 40667

Asia WGS AF: 0.344 AC: 1195 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 22353194, 17640947, 20981092, 16542711) -

Thrombophilia due to activated protein C resistance Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
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. -

Congenital factor V deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	0.012
Dann	Benign	0.70
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.032	T;T
MetaRNN	Benign	0.00014	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-1.2	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.77	N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.0060
MPC		0.087
ClinPred		0.0039	T
GERP RS		-2.9
Varity_R		0.11
gMVP		0.58

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: rs6030; hg19: chr1-169498975; COSMIC: COSV63121507;