rs137852472

Variant names:

• chrX-154837697-G-A
• rs137852472
• NM_000132.4:c.6956C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154837697-G-A
• chrX-154837697-G-C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.6956C>T​(p.Pro2319Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,451 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. P2319S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.96
• Publications: 6 publications found

Genes affected

F8 (HGNC:3546): (coagulation factor VIII) This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder. [provided by RefSeq, Jul 2008]

F8 Gene-Disease associations (from GenCC):

• hemophilia A

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• mild hemophilia A

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• moderately severe hemophilia A

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe hemophilia A

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of hemophilia A in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000132.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154837698-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10147.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 327 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4669 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hemophilia A, mild hemophilia A, symptomatic form of hemophilia A in female carriers, severe hemophilia A, moderately severe hemophilia A.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-154837697-G-A is Pathogenic according to our data. Variant chrX-154837697-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.6956C>T	p.Pro2319Leu	missense_variant	Exon 26 of 26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.551C>T	p.Pro184Leu	missense_variant	Exon 5 of 5		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6956C>T	p.Pro2319Leu	missense_variant	Exon 26 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10	c.551C>T	p.Pro184Leu	missense_variant	Exon 5 of 5	1		ENSP00000327895.6
F8	ENST00000644698.1	c.689C>T	p.Pro230Leu	missense_variant	Exon 6 of 6			ENSP00000495706.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097451 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362813

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841496

Other (OTH) AF: 0.00 AC: 0 AN: 46066

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000907

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 31, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.6956C>T; p.Pro2319Leu variant (rs137852472), also known as Pro2300Leu in traditional nomenclature, is reported in the literature in numerous individuals affected with mild-to-moderate hemophilia A (Higuchi 1991, see link to F8 database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 2319 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.874). Additionally, other variants at this codon (c.6955C>T, p.Pro2319Ser; c.6956C>G, p.Pro2319Arg) have been reported in individuals with hemophilia A and are considered disease-causing (see link to F8 database). Based on available information, the p.Pro2319Leu variant is considered to be pathogenic. References: Link to F8 database: https://f8-db.eahad.org/ Higuchi M et al. Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8307-11. PMID: 1924291. -

Hereditary factor IX deficiency disease Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Hereditary factor VIII deficiency disease Pathogenic:1

Oct 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;H;.
PhyloP100		6.0
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-9.3	D;D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.71
MutPred		0.94		.;Loss of catalytic residue at P2318 (P = 0.0564);.;
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.92
gMVP		1.0
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs137852472; hg19: chrX-154065972;