rs33921347

chrX-154929290-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000132.4(F8):c.4500G>A(p.Pro1500=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,210,190 control chromosomes in the GnomAD database, including 49 homozygotes. There are 808 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., 403 hem., cov: 22)
  • Exomes 𝑓: 0.0014 (30 hom. 405 hem.)
• Consequence: F8 NM_000132.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.256

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-154929290-C-T is Benign according to our data. Variant chrX-154929290-C-T is described in ClinVar as [Benign]. Clinvar id is 255223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154929290-C-T is described in Lovd as [Likely_pathogenic].
• BP7: Synonymous conserved (PhyloP=0.256 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1436/112085) while in subpopulation AFR AF= 0.0449 (1385/30833). AF 95% confidence interval is 0.043. There are 19 homozygotes in gnomad4. There are 403 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.4500G>A	p.Pro1500=	synonymous_variant	14/26	ENST00000360256.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.4500G>A	p.Pro1500=	synonymous_variant	14/26	1	NM_000132.4	P1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1435 AN: 112033 Hom.: 19 Cov.: 22 AF XY: 0.0118 AC XY: 403 AN XY: 34223

Gnomad AFR AF: 0.0450

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00332

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.00666

GnomAD3 exomes AF: 0.00371 AC: 679 AN: 182837 Hom.: 12 AF XY: 0.00234 AC XY: 158 AN XY: 67477

Gnomad AFR exome AF: 0.0467

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000983

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00140 AC: 1537 AN: 1098105 Hom.: 30 Cov.: 33 AF XY: 0.00111 AC XY: 405 AN XY: 363467

Gnomad4 AFR exome AF: 0.0487

Gnomad4 AMR exome AF: 0.00196

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000199

Gnomad4 SAS exome AF: 0.0000739

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000487

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.0128 AC: 1436 AN: 112085 Hom.: 19 Cov.: 22 AF XY: 0.0118 AC XY: 403 AN XY: 34285

Gnomad4 AFR AF: 0.0449

Gnomad4 AMR AF: 0.00331

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000279

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000940

Gnomad4 OTH AF: 0.00657

Alfa AF: 0.0104 Hom.: 38

Bravo AF: 0.0140

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 31, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hereditary factor VIII deficiency disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.46
Cadd	Benign	1.3
Dann	Benign	0.38

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: rs33921347; hg19: chrX-154157565;