NM_000132.4:c.1660A>G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4PP1_StrongPP4_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The c.1660A>G (p.Ser554Gly) missense variant has a REVEL score of 0.938 which meets PP3 criteria (threshold >0.6). This variant is present in 1 hemizygote in gnomAD v2.1.1 and therefore, does not meet criteria for rarity in the population. Fifty-three patients are reported in Johnsen, et. al. 2107 with mild/moderate hemophilia A and the Gly554Ser variant, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate (PMID:29296726). The variant has been found to segregate with hemophilia A across 6 meioses among 4 different families, the PP1 criteria at the strong weight (Internal VCEP contributor). This variant has been reported in individuals who developed an inhibitor to factor replacement therapy and discrepant chromogenic and one-stage factor VIII activity levels (CDC CHAMPS database/Internal VCEP contributor). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very strong, PP1_Strong, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255116/MONDO:0010602/071

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8

Conservation

PhyloP100: 7.03

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.1660A>G	p.Ser554Gly	missense_variant	Exon 11 of 26	ENST00000360256.9	NP_000123.1	P00451-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 link	c.1660A>G	p.Ser554Gly	missense_variant	Exon 11 of 26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000647125.1 link	n.*1536A>G		non_coding_transcript_exon_variant	Exon 12 of 14			ENSP00000496062.1	A0A2R8Y7J7
F8	ENST00000647125 link	n.*1512A>G		3_prime_UTR_variant	Exon 12 of 14			ENSP00000496062.1	A0A2R8Y7J7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183446

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096238

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361630

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Aug 16, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP5, PM1, PM2, PS4_moderate -

Aug 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.1660A>G; p.Ser554Gly variant (rs137852419), also known as Ser535Gly for legacy nomenclature, is reported in multiple individuals with mild hemophilia A (FVIII:C: 3-15 percent) (Diamond 1992, Antonarakis 1995, Liu 2002, Factor VIII database). This variant is also reported in ClinVar (Variation ID: 10226). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 554 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.938). Based on available information, this variant is considered to be pathogenic. References: Factor VIII database link: https://f8-db.eahad.org/index.php Antonarakis SE et al. Molecular etiology of factor VIII deficiency in hemophilia A. Hum Mutat. 1995;5(1):1-22. Diamond C et al. Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. Hum Mutat. 1992;1(3):248-57. Liu ML et al. Non-inversion factor VIII mutations in 80 hemophilia A families including 24 with alloimmune responses. Thromb Haemost. 2002 Feb;87(2):273-6. -

Jun 20, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23711294, 11858487, 19473423, 31361374, 7728145, 1301932) -

Jan 17, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary factor VIII deficiency disease

Pathogenic:3

Feb 02, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1660A>G (p.Ser554Gly) missense variant has a REVEL score of 0.938 which meets PP3 criteria (threshold >0.6). This variant is present in 1 hemizygote in gnomAD v2.1.1 and therefore, does not meet criteria for rarity in the population. Fifty-three patients are reported in Johnsen, et. al. 2107 with mild/moderate hemophilia A and the Gly554Ser variant, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate (PMID: 29296726). The variant has been found to segregate with hemophilia A across 6 meioses among 4 different families, the PP1 criteria at the strong weight (Internal VCEP contributor). This variant has been reported in individuals who developed an inhibitor to factor replacement therapy and discrepant chromogenic and one-stage factor VIII activity levels (CDC CHAMPS database/Internal VCEP contributor). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very strong, PP1_Strong, PP4_Moderate, PP3. -

Aug 08, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: F8 c.1660A>G (p.Ser554Gly) results in a non-conservative amino acid change located in the multicopper oxidase-like, N-terminal domain (IPR011707) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183446 control chromosomes (gnomAD). c.1660A>G (also known as Ser535Gly) has been reported in the literature in multiple individuals affected with mild Factor VIII Deficiency (Hemophilia A) (examples: Diamond_1992 and Miller_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22103590, 1301932). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

F8-related disorder

Pathogenic:1

Mar 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The F8 c.1660A>G variant is predicted to result in the amino acid substitution p.Ser554Gly. This variant, also referred to as p.Ser535Gly using legacy nomenclature, has been reported in individuals with mild to moderate hemophilia A (Diamond et al. 1992. PubMed ID: 1301932; Antonarakis et al. 1995. PubMed ID: 7728145; Liu et al. 2002. PubMed ID: 11858487; F8 database: https://www.factorviii-db.org/index.php). Different missense variants in the same codon (p.Ser554Arg; p.Ser554Cys; p.Ser554Asn) have been reported in individuals with hemophilia A (Feng et al. 2021. PubMed ID: 33245802; Bogdanova et al. 2001. PubMed ID: 11748850; Rydz et al. 2013. PubMed ID: 23913812; F8 database: https://www.factorviii-db.org/index.php). This variant is reported in 0.0036% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.74

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.95

Loss of sheet (P = 0.0181);

MVP

1.0

MPC

1.6

ClinPred

0.95

GERP RS

5.2

Varity_R

0.99

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over