X-154835925-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000132.4(F8):c.*1672G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 110,970 control chromosomes in the GnomAD database, including 14,753 homozygotes. There are 19,046 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (14753 hom., 19046 hem., cov: 23)
  • Exomes 𝑓: 0.50 (0 hom. 0 hem.)
• Consequence: F8 NM_000132.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-154835925-C-T is Benign according to our data. Variant chrX-154835925-C-T is described in ClinVar as [Benign]. Clinvar id is 368105.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154835925-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.*1672G>A		3_prime_UTR_variant	26/26	ENST00000360256.9
F8	NM_019863.3	c.*1672G>A		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.*1672G>A		3_prime_UTR_variant	26/26	1	NM_000132.4	P1
F8	ENST00000330287.10	c.*1672G>A		3_prime_UTR_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 62888 AN: 110916 Hom.: 14756 Cov.: 23 AF XY: 0.574 AC XY: 19032 AN XY: 33180

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.603

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.717

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.583

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 FIN exome AF: 0.500

GnomAD4 genome AF: 0.567 AC: 62893 AN: 110968 Hom.: 14753 Cov.: 23 AF XY: 0.573 AC XY: 19046 AN XY: 33242

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.603

Gnomad4 ASJ AF: 0.661

Gnomad4 EAS AF: 0.796

Gnomad4 SAS AF: 0.574

Gnomad4 FIN AF: 0.780

Gnomad4 NFE AF: 0.734

Gnomad4 OTH AF: 0.588

Alfa AF: 0.684 Hom.: 25340

Bravo AF: 0.544

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	2.2
Dann	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs1050705; hg19: chrX-154064200;