X-154835925-C-T

Variant names:

• chrX-154835925-C-T
• rs1050705
• NM_000132.4:c.*1672G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33
• Publications: 8 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 -20 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 VariationId is 368105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000132.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	NM_000132.4	MANE Select	c.*1672G>A		3_prime_UTR	Exon 26 of 26	NP_000123.1	P00451-1
	F8	NM_019863.3		c.*1672G>A		3_prime_UTR	Exon 5 of 5	NP_063916.1	P00451-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.*1672G>A		3_prime_UTR	Exon 26 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000330287.10	TSL:1	c.*1672G>A		3_prime_UTR	Exon 5 of 5	ENSP00000327895.6	P00451-2
	F8	ENST00000644698.1		c.*1672G>A		downstream_gene	N/A	ENSP00000495706.1	A0A2R8Y707

Frequencies

GnomAD3 genomes AF: 0.567 AC: 62888 AN: 110916 Hom.: 14756 Cov.: 23

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.185 AC: 5666 AN: 30629

American (AMR) AF: 0.603 AC: 6297 AN: 10451

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 1740 AN: 2632

East Asian (EAS) AF: 0.796 AC: 2807 AN: 3525

South Asian (SAS) AF: 0.574 AC: 1515 AN: 2639

European-Finnish (FIN) AF: 0.780 AC: 4550 AN: 5832

Middle Eastern (MID) AF: 0.711 AC: 150 AN: 211

European-Non Finnish (NFE) AF: 0.734 AC: 38787 AN: 52869

Other (OTH) AF: 0.588 AC: 888 AN: 1509

Alfa AF: 0.653 Hom.: 34413

Bravo AF: 0.544

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary factor VIII deficiency disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.2
DANN	Benign	0.36
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs1050705; hg19: chrX-154064200;