rs6027

chr1-169514323-T-C

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.6665A>G(p.Asp2222Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0594 in 1,612,978 control chromosomes in the GnomAD database, including 3,361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (350 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3011 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.84

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=0.009426534).
• BP6: Variant 1-169514323-T-C is Benign according to our data. Variant chr1-169514323-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169514323-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F5	NM_000130.5	c.6665A>G	p.Asp2222Gly	missense_variant	25/25	ENST00000367797.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F5	ENST00000367797.9	c.6665A>G	p.Asp2222Gly	missense_variant	25/25	1	NM_000130.5	P2
F5	ENST00000367796.3	c.6680A>G	p.Asp2227Gly	missense_variant	25/25	5		A2
F5	ENST00000495481.1	n.439A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 8202 AN: 152012 Hom.: 349 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.0750

Gnomad EAS AF: 0.0298

Gnomad SAS AF: 0.0725

Gnomad FIN AF: 0.0853

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0647

Gnomad OTH AF: 0.0637

GnomAD3 exomes AF: 0.0641 AC: 16084 AN: 251060 Hom.: 659 AF XY: 0.0649 AC XY: 8800 AN XY: 135692

Gnomad AFR exome AF: 0.00888

Gnomad AMR exome AF: 0.0938

Gnomad ASJ exome AF: 0.0696

Gnomad EAS exome AF: 0.0296

Gnomad SAS exome AF: 0.0734

Gnomad FIN exome AF: 0.0863

Gnomad NFE exome AF: 0.0611

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0600 AC: 87631 AN: 1460848 Hom.: 3011 Cov.: 31 AF XY: 0.0608 AC XY: 44201 AN XY: 726756

Gnomad4 AFR exome AF: 0.00843

Gnomad4 AMR exome AF: 0.0940

Gnomad4 ASJ exome AF: 0.0690

Gnomad4 EAS exome AF: 0.0594

Gnomad4 SAS exome AF: 0.0730

Gnomad4 FIN exome AF: 0.0841

Gnomad4 NFE exome AF: 0.0579

Gnomad4 OTH exome AF: 0.0582

GnomAD4 genome AF: 0.0539 AC: 8202 AN: 152130 Hom.: 350 Cov.: 32 AF XY: 0.0564 AC XY: 4198 AN XY: 74382

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.0750

Gnomad4 EAS AF: 0.0298

Gnomad4 SAS AF: 0.0723

Gnomad4 FIN AF: 0.0853

Gnomad4 NFE AF: 0.0648

Gnomad4 OTH AF: 0.0630

Alfa AF: 0.0614 Hom.: 850

Bravo AF: 0.0499

TwinsUK AF: 0.0515 AC: 191

ALSPAC AF: 0.0516 AC: 199

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.0617 AC: 531

ExAC AF: 0.0606 AC: 7362

Asia WGS AF: 0.0610 AC: 212 AN: 3478

EpiCase AF: 0.0614

EpiControl AF: 0.0625

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

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, 31399523, 22044617, 14656739, 14695293, 25896652, 20694279) -

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
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0094	T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.000068	P;P
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;.
Vest4		0.41
MPC		0.40
ClinPred		0.012	T
GERP RS		4.9
Varity_R		0.82
gMVP		0.79

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: rs6027; hg19: chr1-169483561; COSMIC: COSV63126354;