X-154837137-C-T

Variant names:

• chrX-154837137-C-T
• rs782195878
• NM_000132.4:c.*460G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000132.4(F8):​c.*460G>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 0.0000444 in 112,632 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000060 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: F8 NM_000132.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.101
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.*460G>A		3_prime_UTR_variant	Exon 26 of 26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.*460G>A		3_prime_UTR_variant	Exon 5 of 5		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.*460G>A		3_prime_UTR_variant	Exon 26 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10	c.*460G>A		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000327895.6
F8	ENST00000644698.1	c.*460G>A		3_prime_UTR_variant	Exon 6 of 6			ENSP00000495706.1

Frequencies

GnomAD3 genomes AF: 0.0000444 AC: 5 AN: 112578 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00138

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000597 AC: 2 AN: 33478 Hom.: 0 Cov.: 0 AF XY: 0.000137 AC XY: 1 AN XY: 7324

African (AFR) AF: 0.00 AC: 0 AN: 1337

American (AMR) AF: 0.00 AC: 0 AN: 2697

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 784

East Asian (EAS) AF: 0.000454 AC: 1 AN: 2203

South Asian (SAS) AF: 0.00 AC: 0 AN: 2620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 99

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 20509

Other (OTH) AF: 0.000535 AC: 1 AN: 1869

GnomAD4 genome AF: 0.0000444 AC: 5 AN: 112632 Hom.: 0 Cov.: 23 AF XY: 0.0000287 AC XY: 1 AN XY: 34796

African (AFR) AF: 0.00 AC: 0 AN: 31038

American (AMR) AF: 0.00 AC: 0 AN: 10651

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00139 AC: 5 AN: 3610

South Asian (SAS) AF: 0.00 AC: 0 AN: 2775

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53320

Other (OTH) AF: 0.00 AC: 0 AN: 1537

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.74
PhyloP100		-0.10

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: rs782195878; hg19: chrX-154065412;