NM_000132.4:c.3864A>C

Variant names:

• chrX-154929926-T-G
• rs1800292
• NM_000132.4:c.3864A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The c.3864A>C (p.Ser1288=) variant is reported at an MAF of 0.3377 (6437/19059 alleles) in the South Asian population in gnomAD v2.1.,1 with 3958 hemizygotes and 424 homozygotes, meeting BA1 criteria of MAF > 0.000333. The synonymous variant is predicted to have no impact on splicing based on SpliceAI score of 0.0, meeting BP4. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343867/MONDO:0010602/071

• Frequency:
  • Genomes: 𝑓 0.10 (553 hom., 3346 hem., cov: 22)
  • Exomes 𝑓: 0.11 (5194 hom. 41809 hem.)
• Consequence: F8 NM_000132.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 0.915
• Publications: 9 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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.3864A>C	p.Ser1288Ser	synonymous	Exon 14 of 26	NP_000123.1	P00451-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.3864A>C	p.Ser1288Ser	synonymous	Exon 14 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000647125.1		n.*3530A>C		downstream_gene	N/A	ENSP00000496062.1	A0A2R8Y7J7

Frequencies

GnomAD3 genomes AF: 0.100 AC: 11138 AN: 111284 Hom.: 555 Cov.: 22

Gnomad AFR AF: 0.0677

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.0506

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.0844

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.147 AC: 26861 AN: 182684 AF XY: 0.155

Gnomad AFR exome AF: 0.0669

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.0578

Gnomad NFE exome AF: 0.0886

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.106 AC: 116489 AN: 1097891 Hom.: 5194 Cov.: 33 AF XY: 0.115 AC XY: 41809 AN XY: 363287

African (AFR) AF: 0.0645 AC: 1703 AN: 26394

American (AMR) AF: 0.252 AC: 8857 AN: 35181

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 3396 AN: 19382

East Asian (EAS) AF: 0.117 AC: 3519 AN: 30203

South Asian (SAS) AF: 0.340 AC: 18410 AN: 54131

European-Finnish (FIN) AF: 0.0612 AC: 2470 AN: 40386

Middle Eastern (MID) AF: 0.233 AC: 962 AN: 4136

European-Non Finnish (NFE) AF: 0.0845 AC: 71175 AN: 841993

Other (OTH) AF: 0.130 AC: 5997 AN: 46085

GnomAD4 genome AF: 0.0999 AC: 11128 AN: 111341 Hom.: 553 Cov.: 22 AF XY: 0.0997 AC XY: 3346 AN XY: 33577

African (AFR) AF: 0.0676 AC: 2076 AN: 30726

American (AMR) AF: 0.193 AC: 2009 AN: 10416

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 476 AN: 2637

East Asian (EAS) AF: 0.163 AC: 572 AN: 3518

South Asian (SAS) AF: 0.347 AC: 903 AN: 2600

European-Finnish (FIN) AF: 0.0506 AC: 306 AN: 6050

Middle Eastern (MID) AF: 0.151 AC: 33 AN: 219

European-Non Finnish (NFE) AF: 0.0845 AC: 4474 AN: 52969

Other (OTH) AF: 0.130 AC: 199 AN: 1526

Alfa AF: 0.0993 Hom.: 4037

Bravo AF: 0.108

EpiCase AF: 0.0980

EpiControl AF: 0.0931

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Hereditary factor VIII deficiency disease (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.1
DANN	Benign	0.59
PhyloP100		0.92
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: rs1800292; hg19: chrX-154158201; COSMIC: COSV64272682; COSMIC: COSV64272682;