rs782198570

Variant names:

• chrX-154861818-T-C
• rs782198570
• NM_000132.4:c.6623A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000132.4(F8):​c.6623A>G​(p.Gln2208Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,208,893 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2208E) has been classified as Pathogenic. The gene F8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000010 (0 hom. 5 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 2.73
• Publications: 0 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

Specifications for F8 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154861819-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 811219.Status of the report is reviewed_by_expert_panel, 3 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 mild hemophilia A, 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, 0.922
• PP5: Variant X-154861818-T-C is Pathogenic according to our data. Variant chrX-154861818-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 368117.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000132.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	NM_000132.4	MANE Select	c.6623A>G	p.Gln2208Arg	missense	Exon 24 of 26	NP_000123.1	P00451-1
	F8	NM_019863.3		c.218A>G	p.Gln73Arg	missense	Exon 3 of 5	NP_063916.1	P00451-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.6623A>G	p.Gln2208Arg	missense	Exon 24 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000330287.10	TSL:1	c.218A>G	p.Gln73Arg	missense	Exon 3 of 5	ENSP00000327895.6	P00451-2
	F8	ENST00000644698.1		c.356A>G	p.Gln119Arg	missense	Exon 4 of 6	ENSP00000495706.1	A0A2R8Y707

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111647 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183405 AF XY: 0.0000295

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097246 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 5 AN XY: 362620

African (AFR) AF: 0.00 AC: 0 AN: 26384

American (AMR) AF: 0.0000284 AC: 1 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54125

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4134

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 841228

Other (OTH) AF: 0.00 AC: 0 AN: 46061

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111647 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33825

African (AFR) AF: 0.00 AC: 0 AN: 30665

American (AMR) AF: 0.00 AC: 0 AN: 10524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00 AC: 0 AN: 2661

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6045

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53134

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.0000543 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary factor VIII deficiency disease (2)
1	-	-	F8-related disorder (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.7
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.74
Sift	Benign	0.041	D
Sift4G	Benign	0.19	T
Polyphen		0.92	P
Vest4		0.39
MutPred		0.83		Gain of MoRF binding (P = 0.0657)
MVP		1.0
MPC		2.0
ClinPred		0.45	T
GERP RS		5.6
Varity_R		0.75
gMVP		0.97
Mutation Taster		=57/43	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782198570; hg19: chrX-154090093;