Variant X-154887398-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012151.4(F8A1):c.1024G>C(p.Val342Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., 0 hem., cov: 15)

Exomes 𝑓: 0.00034 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

F8A1
NM_012151.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.10

Variant links:

Genes affected

F8A1 (HGNC:3547): (coagulation factor VIII associated 1) This gene is contained entirely within intron 22 of the factor VIII gene; spans less than 2 kb, and is transcribed in the direction opposite of factor VIII. A portion of intron 22 (int22h), containing F8A, is repeated twice extragenically closer to the Xq telomere. Although its function is unknown, the observation that this gene is conserved in the mouse implies it has some function. Unlike factor VIII, this gene is transcribed abundantly in a wide variety of cell types. [provided by RefSeq, Jul 2008]

F8A1 links:

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:

MIR1184-1 (HGNC:35265): (microRNA 1184-1) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR1184-1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06479254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
F8A1	NM_012151.4 linkuse as main transcript	c.1024G>C	p.Val342Leu	missense_variant	1/1	ENST00000610495.2	NP_036283.2
F8	NM_000132.4 linkuse as main transcript	c.6429+8679C>G		intron_variant		ENST00000360256.9	NP_000123.1
MIR1184-1	NR_036049.1 linkuse as main transcript	n.61C>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8A1	ENST00000610495.2 linkuse as main transcript	c.1024G>C	p.Val342Leu	missense_variant	1/1		NM_012151.4	ENSP00000479624	P1
F8	ENST00000360256.9 linkuse as main transcript	c.6429+8679C>G		intron_variant		1	NM_000132.4	ENSP00000353393	P1	P00451-1
MIR1184-1	ENST00000408606.1 linkuse as main transcript	n.61C>G		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

71226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

16926

FAILED QC

Gnomad AFR

AF:

0.000476

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000137

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:

0.000777

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000337

AC:

325

AN:

963029

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

285181

show subpopulations

Gnomad4 AFR exome

AF:

0.000373

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000410

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000548

AC:

AN:

71226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

16926

show subpopulations

Gnomad4 AFR

AF:

0.000476

Gnomad4 AMR

AF:

0.000137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000777

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000996

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.1024G>C (p.V342L) alteration is located in exon 1 (coding exon 1) of the F8A1 gene. This alteration results from a G to C substitution at nucleotide position 1024, causing the valine (V) at amino acid position 342 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.025

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.85

M_CAP

Benign

0.0063

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.76

Sift4G

Benign

0.31

Polyphen

0.27

Vest4

0.082

MutPred

0.42

Loss of methylation at K338 (P = 0.0648);

MVP

0.28

ClinPred

0.018

GERP RS

1.5

Varity_R

0.29

gMVP

0.35

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