1-169552693-A-T

Variant names:

• chr1-169552693-A-T
• rs118203911
• NM_000130.5:c.1160T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B.

Score: 8 - Likely Pathogenic

8

PM2PM5PP3_Strong

The NM_000130.5(F5):​c.1160T>A​(p.Ile387Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I387T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.36
• Publications: 0 publications found

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]

F5 Gene-Disease associations (from GenCC):

• thrombophilia due to activated protein C resistance

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• congenital factor V deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• East Texas bleeding disorder

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-169552693-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 655.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5	c.1160T>A	p.Ile387Asn	missense_variant	Exon 8 of 25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.1160T>A	p.Ile387Asn	missense_variant	Exon 8 of 25	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3	c.1160T>A	p.Ile387Asn	missense_variant	Exon 8 of 25	5		ENSP00000356770.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
PhyloP100		8.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.83		Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);
MVP		0.98
MPC		0.63
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.38
gMVP		0.82
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs118203911; hg19: chr1-169521931;