rs1800297

Variant names:

• chrX-154860563-T-C
• rs1800297
• NM_000132.4:c.6769A>G

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The missense variant, NM_000132.3(F8):c.6769A>G (p.Met2257Val), is reported at an MAF of 0.2418 (4578/18936 with 1245 hemizygotes) in the African population in gnomAD v2.1.1. A REVEL score of 0.292 and SpliceAI score of 0 meets BP4 cut-off (respective thresholds <0.3 and <0.05). 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: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343869/MONDO:0010602/071

• Frequency:
  • Genomes: 𝑓 0.068 (621 hom., 2069 hem., cov: 22)
  • Exomes 𝑓: 0.0073 (643 hom. 2076 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 2.30
• Publications: 11 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 -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.6769A>G	p.Met2257Val	missense	Exon 25 of 26	NP_000123.1	P00451-1
	F8	NM_019863.3		c.364A>G	p.Met122Val	missense	Exon 4 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.6769A>G	p.Met2257Val	missense	Exon 25 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000330287.10	TSL:1	c.364A>G	p.Met122Val	missense	Exon 4 of 5	ENSP00000327895.6	P00451-2
	F8	ENST00000644698.1		c.502A>G	p.Met168Val	missense	Exon 5 of 6	ENSP00000495706.1	A0A2R8Y707

Frequencies

GnomAD3 genomes AF: 0.0683 AC: 7621 AN: 111642 Hom.: 621 Cov.: 22

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000564

Gnomad OTH AF: 0.0520

GnomAD2 exomes AF: 0.0195 AC: 3579 AN: 183446 AF XY: 0.0127

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000391

Gnomad OTH exome AF: 0.00728

GnomAD4 exome AF: 0.00729 AC: 8006 AN: 1097919 Hom.: 643 Cov.: 31 AF XY: 0.00571 AC XY: 2076 AN XY: 363277

African (AFR) AF: 0.251 AC: 6620 AN: 26397

American (AMR) AF: 0.0124 AC: 438 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.000480 AC: 26 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00898 AC: 37 AN: 4122

European-Non Finnish (NFE) AF: 0.000211 AC: 178 AN: 841851

Other (OTH) AF: 0.0153 AC: 707 AN: 46081

GnomAD4 genome AF: 0.0683 AC: 7627 AN: 111697 Hom.: 621 Cov.: 22 AF XY: 0.0610 AC XY: 2069 AN XY: 33911

African (AFR) AF: 0.237 AC: 7226 AN: 30548

American (AMR) AF: 0.0277 AC: 291 AN: 10521

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.000374 AC: 1 AN: 2673

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6110

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000564 AC: 30 AN: 53199

Other (OTH) AF: 0.0513 AC: 78 AN: 1519

Alfa AF: 0.0281 Hom.: 1412

Bravo AF: 0.0778

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.237 AC: 908

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0223 AC: 2704

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary factor VIII deficiency disease (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.48	N
PhyloP100		2.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.29
Sift	Benign	0.081	T
Sift4G	Benign	0.36	T
Polyphen		0.24	B
Vest4		0.052
MPC		0.85
ClinPred		0.012	T
GERP RS		4.2
Varity_R		0.49
gMVP		0.79
Mutation Taster		=56/44	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: rs1800297; hg19: chrX-154088838; COSMIC: COSV57705612;