rs6649625

Variant names:

• chrX-155020008-G-A
• rs6649625
• NM_000132.4:c.143+2402C>T

Variant summary

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

The NM_000132.4(F8):​c.143+2402C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 110,604 control chromosomes in the GnomAD database, including 5,997 homozygotes. There are 10,421 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 0.33 (5997 hom., 10421 hem., cov: 23)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• 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=-0.74).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.143+2402C>T		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.143+2402C>T		intron_variant	Intron 1 of 25	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000423959.5	c.38+6772C>T		intron_variant	Intron 1 of 5	3		ENSP00000409446.1
F8	ENST00000453950.1	c.125+2402C>T		intron_variant	Intron 2 of 4	3		ENSP00000389153.1
F8	ENST00000647125.1	n.121+2424C>T		intron_variant	Intron 1 of 13			ENSP00000496062.1

Frequencies

GnomAD3 genomes AF: 0.329 AC: 36422 AN: 110553 Hom.: 5998 Cov.: 23

Gnomad AFR AF: 0.0667

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.0725

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.336

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

GnomAD4 genome AF: 0.329 AC: 36411 AN: 110604 Hom.: 5997 Cov.: 23 AF XY: 0.317 AC XY: 10421 AN XY: 32912

African (AFR) AF: 0.0665 AC: 2034 AN: 30564

American (AMR) AF: 0.259 AC: 2703 AN: 10442

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1321 AN: 2626

East Asian (EAS) AF: 0.0722 AC: 258 AN: 3574

South Asian (SAS) AF: 0.0983 AC: 265 AN: 2695

European-Finnish (FIN) AF: 0.479 AC: 2714 AN: 5668

Middle Eastern (MID) AF: 0.490 AC: 103 AN: 210

European-Non Finnish (NFE) AF: 0.496 AC: 26113 AN: 52640

Other (OTH) AF: 0.332 AC: 503 AN: 1517

Alfa AF: 0.420 Hom.: 20985

Bravo AF: 0.305

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.2
DANN	Benign	0.82
PhyloP100		1.4
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: rs6649625; hg19: chrX-154248283;