rs137852379

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PP5_ModerateBP4BS2

The ENST00000360256.9(F8):c.121G>T(p.Gly41Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,208,566 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G41S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000040 ( 0 hom. 15 hem. )

Consequence

F8
ENST00000360256.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: -0.847

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a domain Plastocyanin-like 1 (size 178) in uniprot entity FA8_HUMAN there are 261 pathogenic changes around while only 2 benign (99%) in ENST00000360256.9

PP5

Variant X-155022432-C-A is Pathogenic according to our data. Variant chrX-155022432-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 10156.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-155022432-C-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.17058894). . Strength limited to SUPPORTING due to the PP5.

BS2

High Hemizygotes in GnomAdExome4 at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4 linkuse as main transcript	c.121G>T	p.Gly41Cys	missense_variant	1/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9 linkuse as main transcript	c.121G>T	p.Gly41Cys	missense_variant	1/26	1	NM_000132.4	ENSP00000353393	P1	P00451-1
F8	ENST00000453950.1 linkuse as main transcript	c.103G>T	p.Gly35Cys	missense_variant	2/5	3		ENSP00000389153
F8	ENST00000423959.5 linkuse as main transcript	c.38+4348G>T		intron_variant		3		ENSP00000409446
F8	ENST00000647125.1 linkuse as main transcript	c.121G>T	p.Asp41Tyr	missense_variant, splice_region_variant, NMD_transcript_variant	1/14			ENSP00000496062

Frequencies

GnomAD3 genomes

AF:

0.0000451

AC:

AN:

110913

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33097

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000336

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000567

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

182769

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

67283

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000521

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.0000401

AC:

AN:

1097653

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363109

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000549

Gnomad4 NFE exome

AF:

0.0000190

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000451

AC:

AN:

110913

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33097

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000336

Gnomad4 NFE

AF:

0.0000567

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000640

Hom.:

ExAC

AF:

0.000123

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1995

- -

Thrombophilia, X-linked, due to factor 8 defect

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Uncertain

0.11

CADD

Benign

5.5

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

T;T

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.43

T;T

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.17

T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.84

N;N

REVEL

Uncertain

0.54

Sift

Uncertain

0.0040

D;D

Sift4G

Benign

0.089

T;.

Polyphen

0.98

D;.

Vest4

0.12

MVP

0.94

MPC

1.3

ClinPred

0.10

GERP RS

-2.2

Varity_R

0.34

gMVP

0.93

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over