X-154966611-C-T

Position:

chrX-154966611-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BA1BP7

This summary comes from the ClinGen Evidence Repository: The c.1086G>A (p.Ala362=) variant is reported at an MAF of 0.03761 (713/18957 alleles) in the African/African-American population in gnomAD v2.1.1 with 201 hemizygotes, meeting BA1 criteria of MAF > 0.000333. SpliceAI predicts no impact on splicing with scores of 0, and the nucleotide is not conserved based on agreement between PhyloP (-2.25) and PhastCons (0) scores meeting BP4 and BP7. 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/F9: BA1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10568504/MONDO:0010602/071

Frequency

Genomes: 𝑓 0.010 ( 15 hom., 312 hem., cov: 22)

Exomes 𝑓: 0.0012 ( 13 hom. 353 hem. )

Consequence

F8
NM_000132.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: -2.19

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4 linkuse as main transcript	c.1086G>A	p.Ala362Ala	synonymous_variant	8/26	ENST00000360256.9	NP_000123.1	P00451-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 linkuse as main transcript	c.1086G>A	p.Ala362Ala	synonymous_variant	8/26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000647125.1 linkuse as main transcript	n.*962G>A		non_coding_transcript_exon_variant	9/14			ENSP00000496062.1	A0A2R8Y7J7
F8	ENST00000647125.1 linkuse as main transcript	n.*962G>A		3_prime_UTR_variant	9/14			ENSP00000496062.1	A0A2R8Y7J7

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1160

AN:

111277

Hom.:

Cov.:

AF XY:

0.00932

AC XY:

312

AN XY:

33481

show subpopulations

Gnomad AFR

AF:

0.0362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00316

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000382

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000754

Gnomad OTH

AF:

0.0107

GnomAD3 exomes

AF:

0.00311

AC:

570

AN:

183332

Hom.:

AF XY:

0.00234

AC XY:

159

AN XY:

67820

show subpopulations

Gnomad AFR exome

AF:

0.0384

Gnomad AMR exome

AF:

0.00172

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad SAS exome

AF:

0.000419

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00116

AC:

1275

AN:

1097652

Hom.:

Cov.:

AF XY:

0.000972

AC XY:

353

AN XY:

363024

show subpopulations

Gnomad4 AFR exome

AF:

0.0396

Gnomad4 AMR exome

AF:

0.00210

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000166

Gnomad4 SAS exome

AF:

0.000240

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000309

Gnomad4 OTH exome

AF:

0.00234

GnomAD4 genome

AF:

0.0104

AC:

1159

AN:

111329

Hom.:

Cov.:

AF XY:

0.00930

AC XY:

312

AN XY:

33543

show subpopulations

Gnomad4 AFR

AF:

0.0361

Gnomad4 AMR

AF:

0.00315

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000383

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000754

Gnomad4 OTH

AF:

0.0106

Alfa

AF:

0.00384

Hom.:

Bravo

AF:

0.0125

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 29, 2023	- -

Hereditary factor VIII deficiency disease

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 01, 2024	The c.1086G>A (p.Ala362=) variant is reported at an MAF of 0.03761 (713/18957 alleles) in the African/African-American population in gnomAD v2.1.1 with 201 hemizygotes, meeting BA1 criteria of MAF > 0.000333. SpliceAI predicts no impact on splicing with scores of 0, and the nucleotide is not conserved based on agreement between PhyloP (-2.25) and PhastCons (0) scores meeting BP4 and BP7. 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/F9: BA1, BP4, BP7. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.7

DANN

Benign

0.34

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