NM_000132.4:c.121G>A

Variant names:

• chrX-155022432-C-T
• rs137852379
• NM_000132.4:c.121G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 5P and 3B. PM1 PM5 PP2 BP4_Moderate BS2_Supporting

The NM_000132.4(F8):​c.121G>A​(p.Gly41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,653 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G41C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.847
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000132.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-155022432-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10156.
• 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=0.076376766).
• BS2: High Hemizygotes in GnomAdExome4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	NM_000132.4	MANE Select	c.121G>A	p.Gly41Ser	missense	Exon 1 of 26	NP_000123.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.121G>A	p.Gly41Ser	missense	Exon 1 of 26	ENSP00000353393.4
	F8	ENST00000453950.1	TSL:3	c.103G>A	p.Gly35Ser	missense	Exon 2 of 5	ENSP00000389153.1
	F8	ENST00000647125.1		n.121G>A		splice_region non_coding_transcript_exon	Exon 1 of 14	ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 182769 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097653 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 363109

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40077

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 842035

Other (OTH) AF: 0.00 AC: 0 AN: 46079

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

F8-related disorder Uncertain:1

Aug 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The F8 c.121G>A variant is predicted to result in the amino acid substitution p.Gly41Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0052% of alleles in individuals of South Asian descent in gnomAD including 1 hemizygous. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	0.16
DANN	Benign	0.62
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.076	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.85
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.0	N
REVEL	Uncertain	0.44
Sift	Benign	0.96	T
Sift4G	Benign	0.82	T
Polyphen		0.0010	B
Vest4		0.019
MutPred		0.41		Gain of sheet (P = 0.0477)
MVP		0.92
MPC		0.64
ClinPred		0.015	T
GERP RS		-2.2
PromoterAI		-0.087	Neutral
Varity_R		0.060
gMVP		0.77
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs137852379; hg19: chrX-154250707; COSMIC: COSV100811532; COSMIC: COSV100811532;