rs1800595

chr1-169541110-T-Cchr1-169541110-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000130.5(F5):c.3980A>G(p.His1327Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0522 in 1,538,076 control chromosomes in the GnomAD database, including 3,267 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (245 hom., cov: 29)
  • Exomes 𝑓: 0.052 (3022 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 1.72

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023017824).
• BP6: Variant 1-169541110-T-C is Benign according to our data. Variant chr1-169541110-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 37345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169541110-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.093 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.3980A>G	p.His1327Arg	missense_variant	13/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.3980A>G	p.His1327Arg	missense_variant	13/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.3995A>G	p.His1332Arg	missense_variant	13/25	5		A2

Frequencies

GnomAD3 genomes AF: 0.0515 AC: 7727 AN: 149898 Hom.: 244 Cov.: 29

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00331

Gnomad AMR AF: 0.0971

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.0266

Gnomad SAS AF: 0.0662

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.0632

GnomAD3 exomes AF: 0.0567 AC: 13974 AN: 246626 Hom.: 584 AF XY: 0.0574 AC XY: 7647 AN XY: 133268

Gnomad AFR exome AF: 0.00747

Gnomad AMR exome AF: 0.0751

Gnomad ASJ exome AF: 0.0623

Gnomad EAS exome AF: 0.0281

Gnomad SAS exome AF: 0.0618

Gnomad FIN exome AF: 0.0799

Gnomad NFE exome AF: 0.0563

Gnomad OTH exome AF: 0.0644

GnomAD4 exome AF: 0.0523 AC: 72579 AN: 1388066 Hom.: 3022 Cov.: 118 AF XY: 0.0537 AC XY: 36986 AN XY: 689074

Gnomad4 AFR exome AF: 0.00810

Gnomad4 AMR exome AF: 0.0799

Gnomad4 ASJ exome AF: 0.0651

Gnomad4 EAS exome AF: 0.0580

Gnomad4 SAS exome AF: 0.0692

Gnomad4 FIN exome AF: 0.0820

Gnomad4 NFE exome AF: 0.0492

Gnomad4 OTH exome AF: 0.0543

GnomAD4 genome AF: 0.0515 AC: 7729 AN: 150010 Hom.: 245 Cov.: 29 AF XY: 0.0534 AC XY: 3911 AN XY: 73246

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.0971

Gnomad4 ASJ AF: 0.0718

Gnomad4 EAS AF: 0.0267

Gnomad4 SAS AF: 0.0663

Gnomad4 FIN AF: 0.0766

Gnomad4 NFE AF: 0.0626

Gnomad4 OTH AF: 0.0630

Alfa AF: 0.0457 Hom.: 102

TwinsUK AF: 0.0539 AC: 200

ALSPAC AF: 0.0529 AC: 204

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.0633 AC: 544

ExAC AF: 0.0611 AC: 7409

Asia WGS AF: 0.0520 AC: 180 AN: 3456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombophilia due to activated protein C resistance Benign:1 Other: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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

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

- -

Factor V deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

This variant is associated with the following publications: (PMID: 33103541, 24175756, 22023244, 9375735, 19652888) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	14
Dann	Benign	0.59
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.025
Sift	Benign	0.054	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.15	B;.
Vest4		0.15
MPC		0.11
ClinPred		0.0033	T
GERP RS		2.2
Varity_R		0.044
gMVP		0.41

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: rs1800595; hg19: chr1-169510348; COSMIC: COSV63124092;