NM_000132.4:c.*78C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000132.4(F8):c.*78C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000801 in 1,094,408 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 253 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.00084 ( 0 hom. 242 hem. )

Consequence

F8
NM_000132.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.258

Publications

0 publications found

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 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

F8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000842 (827/982562) while in subpopulation NFE AF = 0.00106 (797/755248). AF 95% confidence interval is 0.000994. There are 0 homozygotes in GnomAdExome4. There are 242 alleles in the male GnomAdExome4 subpopulation. Median coverage is 19. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.*78C>T		3_prime_UTR_variant	Exon 26 of 26	ENST00000360256.9	NP_000123.1	P00451-1
F8	NM_019863.3 link	c.*78C>T		3_prime_UTR_variant	Exon 5 of 5		NP_063916.1	P00451-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 link	c.*78C>T	3_prime_UTR_variant	Exon 26 of 26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000330287.10 link	c.*78C>T	3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000327895.6	P00451-2
F8	ENST00000644698.1 link	c.*78C>T	3_prime_UTR_variant	Exon 6 of 6			ENSP00000495706.1	A0A2R8Y707

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

111846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000977

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000940

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:

0.000829

Gnomad OTH

AF:

0.00133

GnomAD4 exome

AF:

0.000842

AC:

827

AN:

982562

Hom.:

Cov.:

AF XY:

0.000827

AC XY:

242

AN XY:

292742

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

23712

American (AMR)

AF:

0.00

AC:

AN:

28024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18117

East Asian (EAS)

AF:

0.00

AC:

AN:

27103

South Asian (SAS)

AF:

0.00

AC:

AN:

48195

European-Finnish (FIN)

AF:

0.000161

AC:

AN:

37357

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2816

European-Non Finnish (NFE)

AF:

0.00106

AC:

797

AN:

755248

Other (OTH)

AF:

0.000500

AC:

AN:

41990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

127

159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000447

AC:

AN:

111846

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

34004

show subpopulations

African (AFR)

AF:

0.0000977

AC:

AN:

30691

American (AMR)

AF:

0.0000940

AC:

AN:

10633

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3555

South Asian (SAS)

AF:

0.00

AC:

AN:

2694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000829

AC:

AN:

53091

Other (OTH)

AF:

0.00133

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000486

Hom.:

Bravo

AF:

0.000423

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.1

(source)

DANN

Benign

0.73

PhyloP100

-0.26

Mutation Taster

=100/0

polymorphism

(source)

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

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NM_000132.4:c.*78C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over