X-154837171-C-T

Variant names:

• chrX-154837171-C-T
• rs782273756
• NM_000132.4:c.*426G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000132.4(F8):​c.*426G>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 0.0006 in 173,289 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 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 0.00049 (0 hom., 10 hem., cov: 22)
  • Exomes 𝑓: 0.00080 (0 hom. 14 hem.)
• Consequence: F8 NM_000132.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.660
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS2: High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.*426G>A		3_prime_UTR_variant	Exon 26 of 26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.*426G>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.*426G>A		3_prime_UTR_variant	Exon 26 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10	c.*426G>A		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000327895.6
F8	ENST00000644698.1	c.*426G>A		3_prime_UTR_variant	Exon 6 of 6			ENSP00000495706.1

Frequencies

GnomAD3 genomes AF: 0.000490 AC: 55 AN: 112318 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00416

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000788

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000804 AC: 49 AN: 60971 Hom.: 0 Cov.: 0 AF XY: 0.000951 AC XY: 14 AN XY: 14719

African (AFR) AF: 0.00117 AC: 3 AN: 2560

American (AMR) AF: 0.00117 AC: 4 AN: 3405

Ashkenazi Jewish (ASJ) AF: 0.00321 AC: 5 AN: 1560

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 5346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2889

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.000871 AC: 33 AN: 37875

Other (OTH) AF: 0.00113 AC: 4 AN: 3528

GnomAD4 genome AF: 0.000490 AC: 55 AN: 112318 Hom.: 0 Cov.: 22 AF XY: 0.000290 AC XY: 10 AN XY: 34480

African (AFR) AF: 0.0000647 AC: 2 AN: 30908

American (AMR) AF: 0.00 AC: 0 AN: 10614

Ashkenazi Jewish (ASJ) AF: 0.00416 AC: 11 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3608

South Asian (SAS) AF: 0.00 AC: 0 AN: 2758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6063

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000788 AC: 42 AN: 53283

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.000486 Hom.: 2

Bravo AF: 0.000608

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	-0.92
CADD	Benign	0.78
DANN	Benign	0.62
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism

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: rs782273756; hg19: chrX-154065446;