NM_000132.4:c.389-1780G>A

Variant names:

• chrX-154994928-C-T
• rs5945270
• NM_000132.4:c.389-1780G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000132.4(F8):​c.389-1780G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 112,041 control chromosomes in the GnomAD database, including 66 homozygotes. There are 954 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 0.030 (66 hom., 954 hem., cov: 23)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.694
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0295 (3306/112041) while in subpopulation NFE AF = 0.0425 (2259/53142). AF 95% confidence interval is 0.041. There are 66 homozygotes in GnomAd4. There are 954 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 66 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	NM_000132.4	MANE Select	c.389-1780G>A		intron	N/A	NP_000123.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.389-1780G>A		intron	N/A	ENSP00000353393.4
	F8	ENST00000423959.5	TSL:3	c.284-1780G>A		intron	N/A	ENSP00000409446.1
	F8	ENST00000453950.1	TSL:3	c.371-1780G>A		intron	N/A	ENSP00000389153.1

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 3311 AN: 111988 Hom.: 66 Cov.: 23

Gnomad AFR AF: 0.00532

Gnomad AMI AF: 0.0774

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.0336

Gnomad NFE AF: 0.0425

Gnomad OTH AF: 0.0325

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

GnomAD4 genome AF: 0.0295 AC: 3306 AN: 112041 Hom.: 66 Cov.: 23 AF XY: 0.0279 AC XY: 954 AN XY: 34249

African (AFR) AF: 0.00530 AC: 164 AN: 30920

American (AMR) AF: 0.0139 AC: 147 AN: 10595

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 288 AN: 2645

East Asian (EAS) AF: 0.00140 AC: 5 AN: 3580

South Asian (SAS) AF: 0.0410 AC: 111 AN: 2707

European-Finnish (FIN) AF: 0.0372 AC: 224 AN: 6024

Middle Eastern (MID) AF: 0.0275 AC: 6 AN: 218

European-Non Finnish (NFE) AF: 0.0425 AC: 2259 AN: 53142

Other (OTH) AF: 0.0321 AC: 49 AN: 1525

Alfa AF: 0.0392 Hom.: 287

Bravo AF: 0.0261

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.84
DANN	Benign	0.28
PhyloP100		-0.69
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: rs5945270; hg19: chrX-154223203;