X-154838195-C-T

Variant names:

• chrX-154838195-C-T
• rs17281377
• NM_000132.4:c.6901-443G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000132.4(F8):​c.6901-443G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 111,850 control chromosomes in the GnomAD database, including 248 homozygotes. There are 2,030 hemizygotes in GnomAD. 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 0.064 (248 hom., 2030 hem., cov: 22)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00500
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.6901-443G>A		intron_variant	Intron 25 of 25	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.496-443G>A		intron_variant	Intron 4 of 4		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6901-443G>A		intron_variant	Intron 25 of 25	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10	c.496-443G>A		intron_variant	Intron 4 of 4	1		ENSP00000327895.6
F8	ENST00000644698.1	c.634-443G>A		intron_variant	Intron 5 of 5			ENSP00000495706.1

Frequencies

GnomAD3 genomes AF: 0.0638 AC: 7130 AN: 111796 Hom.: 247 Cov.: 22

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0234

Gnomad AMR AF: 0.0626

Gnomad ASJ AF: 0.0846

Gnomad EAS AF: 0.000558

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.0710

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0976

Gnomad OTH AF: 0.0757

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

GnomAD4 genome AF: 0.0638 AC: 7131 AN: 111850 Hom.: 248 Cov.: 22 AF XY: 0.0596 AC XY: 2030 AN XY: 34060

African (AFR) AF: 0.0137 AC: 424 AN: 30871

American (AMR) AF: 0.0626 AC: 662 AN: 10568

Ashkenazi Jewish (ASJ) AF: 0.0846 AC: 224 AN: 2647

East Asian (EAS) AF: 0.000560 AC: 2 AN: 3572

South Asian (SAS) AF: 0.0224 AC: 60 AN: 2682

European-Finnish (FIN) AF: 0.0710 AC: 426 AN: 5999

Middle Eastern (MID) AF: 0.0913 AC: 20 AN: 219

European-Non Finnish (NFE) AF: 0.0977 AC: 5184 AN: 53082

Other (OTH) AF: 0.0741 AC: 113 AN: 1525

Alfa AF: 0.0818 Hom.: 4761

Bravo AF: 0.0616

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.1
DANN	Benign	0.86
PhyloP100		-0.0050
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: rs17281377; hg19: chrX-154066470;