rs9332701

Variant names:

• chr1-169515529-A-G
• rs9332701
• NM_000130.5:c.6443T>C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000130.5(F5):​c.6443T>C​(p.Met2148Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0422 in 1,613,552 control chromosomes in the GnomAD database, including 1,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (124 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1687 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.76

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 -18 ACMG points.

• PM1: In a domain F5/8 type C 2 (size 155) in uniprot entity FA5_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_000130.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.012470007).
• BP6: Variant 1-169515529-A-G is Benign according to our data. Variant chr1-169515529-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 255214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169515529-A-G is described in Lovd as [Benign]. Variant chr1-169515529-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5	c.6443T>C	p.Met2148Thr	missense_variant	Exon 24 of 25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.6443T>C	p.Met2148Thr	missense_variant	Exon 24 of 25	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3	c.6458T>C	p.Met2153Thr	missense_variant	Exon 24 of 25	5		ENSP00000356770.3
F5	ENST00000495481.1	n.217T>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4632 AN: 152044 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.00858

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0504

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0303 AC: 7611 AN: 251034 Hom.: 163 AF XY: 0.0308 AC XY: 4174 AN XY: 135646

Gnomad AFR exome AF: 0.00806

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0142

Gnomad FIN exome AF: 0.0409

Gnomad NFE exome AF: 0.0471

Gnomad OTH exome AF: 0.0299

GnomAD4 exome AF: 0.0434 AC: 63460 AN: 1461390 Hom.: 1687 Cov.: 32 AF XY: 0.0427 AC XY: 31062 AN XY: 727012

Gnomad4 AFR exome AF: 0.00670

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0149

Gnomad4 FIN exome AF: 0.0418

Gnomad4 NFE exome AF: 0.0506

Gnomad4 OTH exome AF: 0.0394

GnomAD4 genome AF: 0.0304 AC: 4630 AN: 152162 Hom.: 124 Cov.: 32 AF XY: 0.0281 AC XY: 2091 AN XY: 74384

Gnomad4 AFR AF: 0.00855

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0181

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.0392

Gnomad4 NFE AF: 0.0504

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0397 Hom.: 174

Bravo AF: 0.0278

TwinsUK AF: 0.0537 AC: 199

ALSPAC AF: 0.0503 AC: 194

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.0447 AC: 384

ExAC AF: 0.0305 AC: 3707

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0400

EpiControl AF: 0.0435

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Thrombophilia due to activated protein C resistance Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital factor V deficiency Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Budd-Chiari syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Thrombophilia due to thrombin defect Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.012	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;.
Vest4		0.45
MPC		0.50
ClinPred		0.022	T
GERP RS		5.6
Varity_R		0.78
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs9332701; hg19: chr1-169484767;