rs7053448

Variant names:

• chrX-154964936-T-C
• rs7053448
• NM_000132.4:c.1443+1034A>G

Variant summary

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

The NM_000132.4(F8):​c.1443+1034A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 111,285 control chromosomes in the GnomAD database, including 1,007 homozygotes. There are 4,646 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 0.15 (1007 hom., 4646 hem., cov: 23)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 7 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).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.1443+1034A>G		intron_variant	Intron 9 of 25	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.1443+1034A>G		intron_variant	Intron 9 of 25	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*1319+1034A>G		intron_variant	Intron 10 of 13			ENSP00000496062.1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 16625 AN: 111231 Hom.: 1006 Cov.: 23

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.0488

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.149 AC: 16629 AN: 111285 Hom.: 1007 Cov.: 23 AF XY: 0.139 AC XY: 4646 AN XY: 33533

African (AFR) AF: 0.143 AC: 4402 AN: 30685

American (AMR) AF: 0.113 AC: 1188 AN: 10478

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 415 AN: 2633

East Asian (EAS) AF: 0.0530 AC: 190 AN: 3582

South Asian (SAS) AF: 0.0493 AC: 133 AN: 2696

European-Finnish (FIN) AF: 0.154 AC: 915 AN: 5926

Middle Eastern (MID) AF: 0.125 AC: 27 AN: 216

European-Non Finnish (NFE) AF: 0.172 AC: 9070 AN: 52876

Other (OTH) AF: 0.135 AC: 204 AN: 1512

Alfa AF: 0.164 Hom.: 8133

Bravo AF: 0.148

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.55
DANN	Benign	0.62
PhyloP100		-1.3
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: rs7053448; hg19: chrX-154193211;