X-154859093-T-A

Variant names:

• chrX-154859093-T-A
• rs4898399
• NM_000132.4:c.6900+1339A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000360256.9(F8):​c.6900+1339A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.82 (26269 hom., 26368 hem., cov: 21)
  • Failed GnomAD Quality Control
• Consequence: F8 ENST00000360256.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.278
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000360256.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	NM_000132.4	MANE Select	c.6900+1339A>T		intron	N/A	NP_000123.1
	F8	NM_019863.3		c.495+1339A>T		intron	N/A	NP_063916.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.6900+1339A>T		intron	N/A	ENSP00000353393.4
	F8	ENST00000330287.10	TSL:1	c.495+1339A>T		intron	N/A	ENSP00000327895.6
	F8	ENST00000644698.1		c.633+1339A>T		intron	N/A	ENSP00000495706.1

Frequencies

GnomAD3 genomes AF: 0.823 AC: 90094 AN: 109432 Hom.: 26279 Cov.: 21

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.859

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.949

Gnomad FIN AF: 0.861

Gnomad MID AF: 0.916

Gnomad NFE AF: 0.845

Gnomad OTH AF: 0.850

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.823 AC: 90127 AN: 109486 Hom.: 26269 Cov.: 21 AF XY: 0.831 AC XY: 26368 AN XY: 31732

African (AFR) AF: 0.725 AC: 21790 AN: 30061

American (AMR) AF: 0.871 AC: 8920 AN: 10237

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 2398 AN: 2634

East Asian (EAS) AF: 0.956 AC: 3302 AN: 3454

South Asian (SAS) AF: 0.948 AC: 2393 AN: 2524

European-Finnish (FIN) AF: 0.861 AC: 4850 AN: 5635

Middle Eastern (MID) AF: 0.912 AC: 198 AN: 217

European-Non Finnish (NFE) AF: 0.845 AC: 44426 AN: 52561

Other (OTH) AF: 0.854 AC: 1272 AN: 1490

Alfa AF: 0.823 Hom.: 7014

Bravo AF: 0.820

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.4
DANN	Benign	0.65
PhyloP100		-0.28
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: rs4898399; hg19: chrX-154087368;