X-154969895-G-C

Variant names:

• chrX-154969895-G-C
• rs1936645
• NM_000132.4:c.788-343C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000132.4(F8):​c.788-343C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 110,135 control chromosomes in the GnomAD database, including 8,372 homozygotes. There are 12,717 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.40 (8372 hom., 12717 hem., cov: 23)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.68
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant X-154969895-G-C is Benign according to our data. Variant chrX-154969895-G-C is described in ClinVar as Benign. ClinVar VariationId is 1240531.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.788-343C>G		intron_variant	Intron 6 of 25	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.788-343C>G		intron_variant	Intron 6 of 25	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*664-343C>G		intron_variant	Intron 7 of 13			ENSP00000496062.1

Frequencies

GnomAD3 genomes AF: 0.405 AC: 44556 AN: 110083 Hom.: 8371 Cov.: 23

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.406

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.405 AC: 44596 AN: 110135 Hom.: 8372 Cov.: 23 AF XY: 0.392 AC XY: 12717 AN XY: 32449

African (AFR) AF: 0.737 AC: 22278 AN: 30239

American (AMR) AF: 0.377 AC: 3929 AN: 10408

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 890 AN: 2621

East Asian (EAS) AF: 0.216 AC: 754 AN: 3485

South Asian (SAS) AF: 0.405 AC: 1039 AN: 2563

European-Finnish (FIN) AF: 0.212 AC: 1232 AN: 5805

Middle Eastern (MID) AF: 0.306 AC: 66 AN: 216

European-Non Finnish (NFE) AF: 0.259 AC: 13634 AN: 52627

Other (OTH) AF: 0.401 AC: 603 AN: 1505

Alfa AF: 0.358 Hom.: 2458

Bravo AF: 0.427

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-1.7
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: rs1936645; hg19: chrX-154198170;