NM_000132.4:c.7036G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4BS2

The NM_000132.4(F8):c.7036G>A(p.Glu2346Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000025 in 1,201,056 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 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 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000027 ( 0 hom. 10 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.36

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: Likely_benign. The variant received -2 ACMG points.

PM1

In a strand (size 8) in uniprot entity FA8_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 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=0.32010025).

BS2

High Hemizygotes in GnomAdExome4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.7036G>A	p.Glu2346Lys	missense_variant	Exon 26 of 26	ENST00000360256.9	NP_000123.1	P00451-1
F8	NM_019863.3 link	c.631G>A	p.Glu211Lys	missense_variant	Exon 5 of 5		NP_063916.1	P00451-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 link	c.7036G>A	p.Glu2346Lys	missense_variant	Exon 26 of 26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000330287.10 link	c.631G>A	p.Glu211Lys	missense_variant	Exon 5 of 5	1		ENSP00000327895.6	P00451-2
F8	ENST00000644698.1 link	c.769G>A	p.Glu257Lys	missense_variant	Exon 6 of 6			ENSP00000495706.1	A0A2R8Y707

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111405

Hom.:

Cov.:

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000370

AC:

AN:

162054

AF XY:

0.0000591

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000857

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000266

AC:

AN:

1089651

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

357053

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26305

American (AMR)

AF:

0.00

AC:

AN:

34025

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19141

East Asian (EAS)

AF:

0.00

AC:

AN:

29945

South Asian (SAS)

AF:

0.00

AC:

AN:

52604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39997

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4054

European-Non Finnish (NFE)

AF:

0.0000322

AC:

AN:

837776

Other (OTH)

AF:

0.0000437

AC:

AN:

45804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111405

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33593

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30583

American (AMR)

AF:

0.00

AC:

AN:

10584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3549

South Asian (SAS)

AF:

0.00

AC:

AN:

2650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52982

Other (OTH)

AF:

0.00

AC:

AN:

1501

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: F8 c.7036G>A (p.Glu2346Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 162054 control chromosomes, predominantly at a frequency of 8.6e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7036G>A in individuals affected with Factor VIII Deficiency (Hemophilia A) and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

.;D;.

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.81

T;T;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.6

.;L;.

PhyloP100

2.4

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.6

D;D;.

REVEL

Uncertain

0.37

Sift

Benign

0.031

D;D;.

Sift4G

Benign

0.45

T;D;.

Polyphen

0.94

.;P;.

Vest4

0.24

MVP

0.91

MPC

1.1

ClinPred

0.15

GERP RS

3.9

Varity_R

0.46

gMVP

0.97

Mutation Taster

=77/23

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_000132.4:c.7036G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over