X-154945255-G-T

Variant names:

• chrX-154945255-G-T
• rs6643622
• NM_000132.4:c.2113+2443C>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.2113+2443C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 109,504 control chromosomes in the GnomAD database, including 13,306 homozygotes. There are 17,413 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 0.54 (13306 hom., 17413 hem., cov: 22)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123
• Publications: 3 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 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.2113+2443C>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.2113+2443C>A		intron	N/A	ENSP00000353393.4	P00451-1
	F8	ENST00000647125.1		n.*1779+8637C>A		intron	N/A	ENSP00000496062.1	A0A2R8Y7J7

Frequencies

GnomAD3 genomes AF: 0.539 AC: 59002 AN: 109464 Hom.: 13307 Cov.: 22

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.731

Gnomad MID AF: 0.686

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.555

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

GnomAD4 genome AF: 0.539 AC: 59003 AN: 109504 Hom.: 13306 Cov.: 22 AF XY: 0.547 AC XY: 17413 AN XY: 31852

African (AFR) AF: 0.174 AC: 5246 AN: 30190

American (AMR) AF: 0.594 AC: 6112 AN: 10290

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 1646 AN: 2598

East Asian (EAS) AF: 0.780 AC: 2707 AN: 3472

South Asian (SAS) AF: 0.566 AC: 1421 AN: 2509

European-Finnish (FIN) AF: 0.731 AC: 4170 AN: 5701

Middle Eastern (MID) AF: 0.686 AC: 142 AN: 207

European-Non Finnish (NFE) AF: 0.692 AC: 36256 AN: 52376

Other (OTH) AF: 0.560 AC: 833 AN: 1487

Alfa AF: 0.617 Hom.: 43670

Bravo AF: 0.519

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.4
DANN	Benign	0.42
PhyloP100		0.12
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: rs6643622; hg19: chrX-154173530;