NM_000132.4:c.144-5899T>C

Variant names:

• chrX-155005499-A-G
• rs17281398
• NM_000132.4:c.144-5899T>C

Variant summary

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

The NM_000132.4(F8):​c.144-5899T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0659 in 110,770 control chromosomes in the GnomAD database, including 255 homozygotes. There are 2,024 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 0.066 (255 hom., 2024 hem., cov: 21)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.244
• Publications: 5 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0984 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.144-5899T>C		intron_variant	Intron 1 of 25	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.144-5899T>C		intron_variant	Intron 1 of 25	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000423959.5	c.39-5899T>C		intron_variant	Intron 1 of 5	3		ENSP00000409446.1
F8	ENST00000453950.1	c.126-5899T>C		intron_variant	Intron 2 of 4	3		ENSP00000389153.1
F8	ENST00000647125.1	n.122-5899T>C		intron_variant	Intron 1 of 13			ENSP00000496062.1

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 7300 AN: 110718 Hom.: 254 Cov.: 21

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.0236

Gnomad AMR AF: 0.0621

Gnomad ASJ AF: 0.0855

Gnomad EAS AF: 0.000567

Gnomad SAS AF: 0.0285

Gnomad FIN AF: 0.0775

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0753

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

GnomAD4 genome AF: 0.0659 AC: 7302 AN: 110770 Hom.: 255 Cov.: 21 AF XY: 0.0614 AC XY: 2024 AN XY: 32988

African (AFR) AF: 0.0139 AC: 422 AN: 30434

American (AMR) AF: 0.0621 AC: 650 AN: 10464

Ashkenazi Jewish (ASJ) AF: 0.0855 AC: 225 AN: 2633

East Asian (EAS) AF: 0.000569 AC: 2 AN: 3518

South Asian (SAS) AF: 0.0294 AC: 75 AN: 2555

European-Finnish (FIN) AF: 0.0775 AC: 460 AN: 5933

Middle Eastern (MID) AF: 0.111 AC: 24 AN: 217

European-Non Finnish (NFE) AF: 0.101 AC: 5316 AN: 52820

Other (OTH) AF: 0.0737 AC: 112 AN: 1519

Alfa AF: 0.0739 Hom.: 2286

Bravo AF: 0.0632

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.86
DANN	Benign	0.69
PhyloP100		-0.24
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: rs17281398; hg19: chrX-154233774;