rs1800291

Variant names:

• chrX-154930010-G-C
• rs1800291
• NM_000132.4:c.3780C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-154930010-G-C
• chrX-154930010-G-A
• chrX-154930010-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000132.4(F8):​c.3780C>G​(p.Asp1260Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,207,733 control chromosomes in the GnomAD database, including 20,423 homozygotes. There are 70,527 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (5548 hom., 9023 hem., cov: 22)
  • Exomes 𝑓: 0.18 (14875 hom. 61504 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.400
• Publications: 34 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 -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 327 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4669 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hemophilia A, mild hemophilia A, symptomatic form of hemophilia A in female carriers, severe hemophilia A, moderately severe hemophilia A.
• BP4: Computational evidence support a benign effect (MetaRNN=6.852606E-6).
• BP6: Variant X-154930010-G-C is Benign according to our data. Variant chrX-154930010-G-C is described in ClinVar as Benign. ClinVar VariationId is 40999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.641 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.3780C>G	p.Asp1260Glu	missense	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.3780C>G	p.Asp1260Glu	missense	Exon 14 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000647125.1		n.*3446C>G		downstream_gene	N/A	ENSP00000496062.1	A0A2R8Y7J7

Frequencies

GnomAD3 genomes AF: 0.296 AC: 32725 AN: 110565 Hom.: 5547 Cov.: 22

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0517

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.258

GnomAD2 exomes AF: 0.184 AC: 33480 AN: 182390 AF XY: 0.161

Gnomad AFR exome AF: 0.664

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0481

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.178 AC: 194786 AN: 1097115 Hom.: 14875 Cov.: 33 AF XY: 0.170 AC XY: 61504 AN XY: 362629

African (AFR) AF: 0.661 AC: 17452 AN: 26392

American (AMR) AF: 0.182 AC: 6407 AN: 35159

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 2698 AN: 19380

East Asian (EAS) AF: 0.0745 AC: 2250 AN: 30193

South Asian (SAS) AF: 0.0548 AC: 2964 AN: 54127

European-Finnish (FIN) AF: 0.168 AC: 6773 AN: 40360

Middle Eastern (MID) AF: 0.139 AC: 573 AN: 4137

European-Non Finnish (NFE) AF: 0.175 AC: 147119 AN: 841319

Other (OTH) AF: 0.186 AC: 8550 AN: 46048

GnomAD4 genome AF: 0.296 AC: 32765 AN: 110618 Hom.: 5548 Cov.: 22 AF XY: 0.274 AC XY: 9023 AN XY: 32888

African (AFR) AF: 0.648 AC: 19646 AN: 30313

American (AMR) AF: 0.181 AC: 1881 AN: 10416

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 410 AN: 2629

East Asian (EAS) AF: 0.0518 AC: 183 AN: 3531

South Asian (SAS) AF: 0.0507 AC: 135 AN: 2664

European-Finnish (FIN) AF: 0.155 AC: 905 AN: 5825

Middle Eastern (MID) AF: 0.140 AC: 30 AN: 214

European-Non Finnish (NFE) AF: 0.172 AC: 9104 AN: 52837

Other (OTH) AF: 0.254 AC: 384 AN: 1510

Alfa AF: 0.159 Hom.: 3943

Bravo AF: 0.316

TwinsUK AF: 0.174 AC: 647

ALSPAC AF: 0.169 AC: 487

ESP6500AA AF: 0.650 AC: 2492

ESP6500EA AF: 0.174 AC: 1168

ExAC AF: 0.184 AC: 22360

EpiCase AF: 0.164

EpiControl AF: 0.161

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.037
DANN	Benign	0.11
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.00082	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000068	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.40
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.94	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0070
MutPred		0.096		Gain of disorder (P = 0.1105)
MPC		0.044
ClinPred		0.00047	T
GERP RS		0.78
Varity_R		0.037
gMVP		0.19
Mutation Taster		=97/3	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: rs1800291; hg19: chrX-154158285; COSMIC: COSV64273830; COSMIC: COSV64273830;