rs5945269

Variant names:

• chrX-154991043-A-G
• rs5945269
• NM_000132.4:c.601+1893T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000132.4(F8):​c.601+1893T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 111,558 control chromosomes in the GnomAD database, including 1,712 homozygotes. There are 5,663 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.18 (1712 hom., 5663 hem., cov: 22)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.109
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-154991043-A-G is Benign according to our data. Variant chrX-154991043-A-G is described in CliVar as Benign. Clinvar id is 1297951.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154991043-A-G is described in CliVar as Benign. Clinvar id is 1297951.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154991043-A-G is described in CliVar as Benign. Clinvar id is 1297951.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.601+1893T>C		intron_variant	Intron 4 of 25	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.601+1893T>C		intron_variant	Intron 4 of 25	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000423959.5	c.496+1893T>C		intron_variant	Intron 4 of 5	3		ENSP00000409446.1
F8	ENST00000647125.1	n.*387+1893T>C		intron_variant	Intron 4 of 13			ENSP00000496062.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 20218 AN: 111503 Hom.: 1710 Cov.: 22

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0900

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.0488

Gnomad SAS AF: 0.0958

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0921

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.147

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

GnomAD4 genome AF: 0.181 AC: 20228 AN: 111558 Hom.: 1712 Cov.: 22 AF XY: 0.167 AC XY: 5663 AN XY: 33820

African (AFR) AF: 0.324 AC: 9926 AN: 30616

American (AMR) AF: 0.0898 AC: 949 AN: 10569

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 443 AN: 2636

East Asian (EAS) AF: 0.0495 AC: 176 AN: 3559

South Asian (SAS) AF: 0.0949 AC: 254 AN: 2676

European-Finnish (FIN) AF: 0.113 AC: 685 AN: 6054

Middle Eastern (MID) AF: 0.0826 AC: 18 AN: 218

European-Non Finnish (NFE) AF: 0.141 AC: 7489 AN: 53033

Other (OTH) AF: 0.146 AC: 221 AN: 1518

Alfa AF: 0.164 Hom.: 4676

Bravo AF: 0.186

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.54
PhyloP100		-0.11
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: rs5945269; hg19: chrX-154219318;