rs4074307

Variant names:

• chrX-154901948-A-G
• rs4074307
• NM_000132.4:c.6115+103T>C

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.6115+103T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 584,885 control chromosomes in the GnomAD database, including 26,012 homozygotes. There are 65,023 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (9728 hom., 13202 hem., cov: 22)
  • Exomes 𝑓: 0.30 (16284 hom. 51821 hem.)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.411
• Publications: 3 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=-0.88).
• BP6: Variant X-154901948-A-G is Benign according to our data. Variant chrX-154901948-A-G is described in ClinVar as Benign. ClinVar VariationId is 1253881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.6115+103T>C		intron_variant	Intron 19 of 25	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6115+103T>C		intron_variant	Intron 19 of 25	1	NM_000132.4	ENSP00000353393.4

Frequencies

GnomAD3 genomes AF: 0.426 AC: 46928 AN: 110253 Hom.: 9727 Cov.: 22

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.289

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.414

GnomAD4 exome AF: 0.304 AC: 144083 AN: 474575 Hom.: 16284 AF XY: 0.308 AC XY: 51821 AN XY: 168477

African (AFR) AF: 0.810 AC: 11543 AN: 14242

American (AMR) AF: 0.446 AC: 15027 AN: 33728

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 4894 AN: 15248

East Asian (EAS) AF: 0.177 AC: 4792 AN: 27099

South Asian (SAS) AF: 0.401 AC: 16682 AN: 41555

European-Finnish (FIN) AF: 0.233 AC: 9188 AN: 39509

Middle Eastern (MID) AF: 0.365 AC: 1057 AN: 2898

European-Non Finnish (NFE) AF: 0.264 AC: 72693 AN: 274990

Other (OTH) AF: 0.324 AC: 8207 AN: 25306

GnomAD4 genome AF: 0.426 AC: 46977 AN: 110310 Hom.: 9728 Cov.: 22 AF XY: 0.405 AC XY: 13202 AN XY: 32584

African (AFR) AF: 0.809 AC: 24402 AN: 30154

American (AMR) AF: 0.387 AC: 3994 AN: 10332

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 894 AN: 2633

East Asian (EAS) AF: 0.196 AC: 692 AN: 3536

South Asian (SAS) AF: 0.398 AC: 1038 AN: 2611

European-Finnish (FIN) AF: 0.208 AC: 1217 AN: 5838

Middle Eastern (MID) AF: 0.294 AC: 63 AN: 214

European-Non Finnish (NFE) AF: 0.263 AC: 13901 AN: 52814

Other (OTH) AF: 0.408 AC: 616 AN: 1509

Alfa AF: 0.319 Hom.: 12359

Bravo AF: 0.455

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.85
PhyloP100		-0.41
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: rs4074307; hg19: chrX-154130223;