X-154930152-AT-ATT

Variant names:

• chrX-154930152-A-AT
• rs387906450
• NM_000132.4:c.3637dupA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000132.4(F8):​c.3637dupA​(p.Ile1213AsnfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,088,214 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: F8 NM_000132.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.516

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-154930152-A-AT is Pathogenic according to our data. Variant chrX-154930152-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1330420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.3637dupA	p.Ile1213AsnfsTer28	frameshift_variant	Exon 14 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.3637dupA	p.Ile1213AsnfsTer28	frameshift_variant	Exon 14 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*3303dupA		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 14			ENSP00000496062.1
F8	ENST00000647125	n.*3279dupA		3_prime_UTR_variant	Exon 14 of 14			ENSP00000496062.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 110563 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33037 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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 AF: 0.00000551 AC: 6 AN: 1088214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 356088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000718

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 110610 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33094

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Dec 05, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.3637dupA; p.Ile1213AsnfsTer28 variant (rs387906450), also known as codon 1191-1194 insA, 3629insA or 3809insA, is reported in multiple individuals with severe or moderate hemophilia A (Pieneman 1995, Nakaya 2001, Factor VIII database and references therein). This variant is found in the general population with an overall allele frequency of 0.005% (8/163970 alleles) in the Genome Aggregation Database. This variant causes a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Factor VIII database: https://f8-db.eahad.org/ Nakaya S et al. Some factor VIII exon 14 frameshift mutations cause moderately severe haemophilia A. Br J Haematol. 2001 Dec;115(4):977-82. Pieneman WC et al. Screening for mutations in haemophilia A patients by multiplex PCR-SSCP, Southern blotting and RNA analysis: the detection of a genetic abnormality in the factor VIII gene in 30 out of 35 patients. Br J Haematol. 1995 Jun;90(2):442-9. -

Hereditary factor VIII deficiency disease Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift variant c.3637dup(p.Ile1213AsnfsTer28) in F8 gene has been reported in multiple individuals affected with Hemophilia A (Nakaya et. al., 2001; Pieneman et. al., 1995). The observed variant has allele frequency of 0.005% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Isoleucine 1213, changes this amino acid to Asparagine residue, and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Ile1213AsnfsTer28. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. However, additional functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs387906450; hg19: chrX-154158427;