X-154836305-T-C

Variant names:

• chrX-154836305-T-C
• rs1396947
• NM_000132.4:c.*1292A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000132.4(F8):​c.*1292A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene F8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.99 (38426 hom., 32204 hem., cov: 22)
  • Exomes 𝑓: 1.0 (1 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: F8 NM_000132.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 4 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

Specifications for F8 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 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.*1292A>G		3_prime_UTR	Exon 26 of 26	NP_000123.1	P00451-1
	F8	NM_019863.3		c.*1292A>G		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.*1292A>G		3_prime_UTR	Exon 26 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000330287.10	TSL:1	c.*1292A>G		3_prime_UTR	Exon 5 of 5	ENSP00000327895.6	P00451-2
	F8	ENST00000644698.1		c.*1292A>G		3_prime_UTR	Exon 6 of 6	ENSP00000495706.1	A0A2R8Y707

Frequencies

GnomAD3 genomes AF: 0.994 AC: 109478 AN: 110136 Hom.: 38430 Cov.: 22

Gnomad AFR AF: 0.980

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.994

GnomAD4 exome AF: 1.00 AC: 3 AN: 3 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 1 AN XY: 1

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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AF: 1.00 AC: 1 AN: 1

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.994 AC: 109532 AN: 110191 Hom.: 38426 Cov.: 22 AF XY: 0.995 AC XY: 32204 AN XY: 32379

African (AFR) AF: 0.980 AC: 29652 AN: 30246

American (AMR) AF: 0.995 AC: 10213 AN: 10268

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2630 AN: 2630

East Asian (EAS) AF: 1.00 AC: 3515 AN: 3515

South Asian (SAS) AF: 1.00 AC: 2563 AN: 2563

European-Finnish (FIN) AF: 1.00 AC: 5728 AN: 5728

Middle Eastern (MID) AF: 1.00 AC: 214 AN: 214

European-Non Finnish (NFE) AF: 1.00 AC: 52855 AN: 52856

Other (OTH) AF: 0.994 AC: 1478 AN: 1487

Alfa AF: 0.997 Hom.: 9222

Bravo AF: 0.993

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.65
DANN	Benign	0.81
PhyloP100		-1.2
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: rs1396947; hg19: chrX-154064580;