rs118203906

Positions:

• chr1-169555299-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM5 PP3_Moderate PP5_Moderate BS1_Supporting BS2_Supporting

The ENST00000367797.9(F5):​c.1001G>C​(p.Arg334Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,614,068 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: F5 ENST00000367797.9 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.301

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 Uncertain_significance. Variant got 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-169555300-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 1-169555299-C-G is Pathogenic according to our data. Variant chr1-169555299-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 644.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-169555299-C-G is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00013 (190/1461852) while in subpopulation MID AF= 0.00191 (11/5768). AF 95% confidence interval is 0.00107. There are 2 homozygotes in gnomad4_exome. There are 97 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F5	NM_000130.5	c.1001G>C	p.Arg334Thr	missense_variant	7/25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.1001G>C	p.Arg334Thr	missense_variant	7/25	1	NM_000130.5	ENSP00000356771	P2
F5	ENST00000367796.3	c.1001G>C	p.Arg334Thr	missense_variant	7/25	5		ENSP00000356770	A2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152098 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 251352 Hom.: 1 AF XY: 0.000213 AC XY: 29 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000130 AC: 190 AN: 1461852 Hom.: 2 Cov.: 31 AF XY: 0.000133 AC XY: 97 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000556

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000818

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152216 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4 AN XY: 74428

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombophilia due to activated protein C resistance Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Apr 16, 2021	This variant was previously reported in a proximal deep vein thrombosis patient of British origin and was also identified in his mother, who presented with abnormally low APC resistance value. It was not found in 600 other individuals presenting with thromboembolism or in a population of normal blood donors, suggesting that it is a rare factor V variant [PMID: 9454742]. This variant was previously represented as either p.R306T/Arg306Thr or F5 Cambridge in the cited articles. Another missense substitution affecting this residue p. Arg334Gly (referred as Arg306Gly FV Hong Kong) was previously identified in 2 thrombotic patients and 1 nonthrombotic subject of Chinese origin [PMID: 9454741]. Previously this variant was reported to affect the cleavage site responsible for the complete loss of F5 procoagulant activity suggesting its possible contribution to APC resistance [PMID: 30630204, 7989361]. However, invitro recombinant cells harboring this variant revealed intermediate APC resistance patterns between those of wild type factor V and other well-known F5 Leiden (Arg506) variant, suggesting low thrombotic risk association [PMID:12091344]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 1998	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.00080	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.2e-9	A;A;A
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.66
Sift	Benign	0.14	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.98	D;.
Vest4		0.67
MVP		0.81
MPC		0.57
ClinPred		0.088	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.67

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: rs118203906; hg19: chr1-169524537;