rs137852388

Variant names:

• chrX-154993141-T-G
• rs137852388
• NM_000132.4:c.396A>C
• F8 p.Glu132Asp

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4 BS2_Supporting

The NM_000132.4(F8):​c.396A>C​(p.Glu132Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,206,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 113 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene F8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00029 (0 hom. 108 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 B:4
• Conservation: PhyloP100: -0.342
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000132.4
• 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 mild hemophilia A, 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=0.2800225).
• BS2: High Hemizygotes in GnomAd4 at 5 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.396A>C	p.Glu132Asp	missense	Exon 4 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.396A>C	p.Glu132Asp	missense	Exon 4 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000423959.5	TSL:3	c.291A>C	p.Glu97Asp	missense	Exon 4 of 6	ENSP00000409446.1	B1B0G8
	F8	ENST00000453950.1	TSL:3	c.378A>C	p.Glu126Asp	missense	Exon 5 of 5	ENSP00000389153.1	B1B0G9

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 23 AN: 112782 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000394

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000176 AC: 32 AN: 182311 AF XY: 0.000179

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000357

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000286 AC: 313 AN: 1093906 Hom.: 0 Cov.: 29 AF XY: 0.000301 AC XY: 108 AN XY: 359350

African (AFR) AF: 0.0000380 AC: 1 AN: 26314

American (AMR) AF: 0.000227 AC: 8 AN: 35167

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19341

East Asian (EAS) AF: 0.00 AC: 0 AN: 30183

South Asian (SAS) AF: 0.00 AC: 0 AN: 53974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40506

Middle Eastern (MID) AF: 0.000495 AC: 2 AN: 4043

European-Non Finnish (NFE) AF: 0.000349 AC: 293 AN: 838432

Other (OTH) AF: 0.000196 AC: 9 AN: 45946

GnomAD4 genome AF: 0.000204 AC: 23 AN: 112836 Hom.: 0 Cov.: 23 AF XY: 0.000143 AC XY: 5 AN XY: 34978

African (AFR) AF: 0.00 AC: 0 AN: 31086

American (AMR) AF: 0.000187 AC: 2 AN: 10719

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3610

South Asian (SAS) AF: 0.00 AC: 0 AN: 2747

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000394 AC: 21 AN: 53339

Other (OTH) AF: 0.00 AC: 0 AN: 1536

Alfa AF: 0.000155 Hom.: 1

Bravo AF: 0.000189

EpiCase AF: 0.000654

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	2	Hereditary factor VIII deficiency disease (4)
1	-	-	F8-related disorder (1)
-	-	1	Hemorrhage (1)
1	-	-	Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect (1)
-	1	-	not provided (1)
-	-	1	not specified (1)
1	-	-	Thrombophilia, X-linked, due to factor 8 defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	9.4
DANN	Benign	0.97
DEOGEN2	Uncertain	0.70	D
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.28	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	0.73	N
PhyloP100		-0.34
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.95	N
REVEL	Pathogenic	0.68
Sift	Benign	0.34	T
Sift4G	Benign	0.55	T
Varity_R		0.38
gMVP		0.98
Mutation Taster		=68/32	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs137852388;

hg19: chrX-154221416;