rs4898352

Variant names:

• chrX-154903815-A-T
• rs4898352
• NM_000132.4:c.5998+91T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000132.4(F8):​c.5998+91T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 775,751 control chromosomes in the GnomAD database, including 33,605 homozygotes. There are 71,495 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene F8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.43 (9839 hom., 13681 hem., cov: 23)
  • Exomes 𝑓: 0.30 (23766 hom. 57814 hem.)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.384
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant X-154903815-A-T is Benign according to our data. Variant chrX-154903815-A-T is described in ClinVar as Benign. ClinVar VariationId is 1251259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

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.5998+91T>A		intron	N/A	NP_000123.1	P00451-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.5998+91T>A		intron	N/A	ENSP00000353393.4	P00451-1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 47554 AN: 111046 Hom.: 9838 Cov.: 23

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.412

GnomAD4 exome AF: 0.299 AC: 198409 AN: 664652 Hom.: 23766 AF XY: 0.308 AC XY: 57814 AN XY: 187544

African (AFR) AF: 0.823 AC: 14940 AN: 18155

American (AMR) AF: 0.441 AC: 14463 AN: 32820

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 5089 AN: 15880

East Asian (EAS) AF: 0.178 AC: 4961 AN: 27812

South Asian (SAS) AF: 0.397 AC: 16936 AN: 42625

European-Finnish (FIN) AF: 0.233 AC: 9127 AN: 39243

Middle Eastern (MID) AF: 0.368 AC: 1101 AN: 2992

European-Non Finnish (NFE) AF: 0.268 AC: 121699 AN: 453878

Other (OTH) AF: 0.323 AC: 10093 AN: 31247

GnomAD4 genome AF: 0.428 AC: 47598 AN: 111099 Hom.: 9839 Cov.: 23 AF XY: 0.411 AC XY: 13681 AN XY: 33303

African (AFR) AF: 0.816 AC: 24809 AN: 30417

American (AMR) AF: 0.388 AC: 4069 AN: 10474

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 884 AN: 2626

East Asian (EAS) AF: 0.196 AC: 695 AN: 3547

South Asian (SAS) AF: 0.407 AC: 1078 AN: 2646

European-Finnish (FIN) AF: 0.215 AC: 1288 AN: 6002

Middle Eastern (MID) AF: 0.282 AC: 61 AN: 216

European-Non Finnish (NFE) AF: 0.263 AC: 13937 AN: 52976

Other (OTH) AF: 0.406 AC: 616 AN: 1518

Alfa AF: 0.364 Hom.: 2849

Bravo AF: 0.456

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.68
DANN	Benign	0.76
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs4898352; hg19: chrX-154132090;