X-154887398-G-C

Variant names:

• chrX-154887398-G-C
• rs1472713003
• NM_012151.4:c.1024G>C

Variant summary

Our verdict is Likely benign. The variant received -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. 10/16 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10
• Publications: 0 publications found

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]

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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06479254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8A1	NM_012151.4	c.1024G>C	p.Val342Leu	missense_variant	Exon 1 of 1	ENST00000610495.2	NP_036283.2
F8	NM_000132.4	c.6429+8679C>G		intron_variant	Intron 22 of 25	ENST00000360256.9	NP_000123.1
MIR1184-1	NR_036049.1	n.61C>G		non_coding_transcript_exon_variant	Exon 1 of 1
MIR1184-1	unassigned_transcript_3892	n.1C>G		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8A1	ENST00000610495.2	c.1024G>C	p.Val342Leu	missense_variant	Exon 1 of 1	6	NM_012151.4	ENSP00000479624.1
F8	ENST00000360256.9	c.6429+8679C>G		intron_variant	Intron 22 of 25	1	NM_000132.4	ENSP00000353393.4
MIR1184-1	ENST00000408606.1	n.61C>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.000548 AC: 39 AN: 71226 Hom.: 0 Cov.: 15

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

GnomAD2 exomes AF: 0.000304 AC: 9 AN: 29635 AF XY: 0.00

Gnomad AFR exome AF: 0.00253

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: 0.000549

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000337 AC: 325 AN: 963029 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 285181

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

African (AFR) AF: 0.000373 AC: 4 AN: 10731

American (AMR) AF: 0.0000671 AC: 2 AN: 29806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18127

East Asian (EAS) AF: 0.00 AC: 0 AN: 27825

South Asian (SAS) AF: 0.00 AC: 0 AN: 47471

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38215

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2568

European-Non Finnish (NFE) AF: 0.000410 AC: 307 AN: 747995

Other (OTH) AF: 0.000298 AC: 12 AN: 40291

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000548 AC: 39 AN: 71226 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 16926

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

African (AFR) AF: 0.000476 AC: 3 AN: 6300

American (AMR) AF: 0.000137 AC: 1 AN: 7273

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2271

East Asian (EAS) AF: 0.00 AC: 0 AN: 2307

South Asian (SAS) AF: 0.00 AC: 0 AN: 1712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 209

European-Non Finnish (NFE) AF: 0.000777 AC: 35 AN: 45035

Other (OTH) AF: 0.00 AC: 0 AN: 1042

⚠️ 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.

Alfa AF: 0.000996 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.31	T
Polyphen		0.27	B
Vest4		0.082
MutPred		0.42		Loss of methylation at K338 (P = 0.0648);
MVP		0.28
ClinPred		0.018	T
GERP RS		1.5
Varity_R		0.29
gMVP		0.35
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1472713003; hg19: chrX-154115673; COSMIC: COSV106096805; COSMIC: COSV106096805;