X-154887209-C-G

Variant names:

• chrX-154887209-C-G
• rs1453070252
• NM_012151.4:c.835C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012151.4(F8A1):​c.835C>G​(p.Leu279Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 0 hem., cov: 4)
  • Exomes 𝑓: 0.000094 (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: 0.838
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11622617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8A1	NM_012151.4	c.835C>G	p.Leu279Val	missense_variant	Exon 1 of 1	ENST00000610495.2	NP_036283.2
F8	NM_000132.4	c.6429+8868G>C		intron_variant	Intron 22 of 25	ENST00000360256.9	NP_000123.1
MIR1184-1	NR_036049.1	n.*151G>C		downstream_gene_variant
MIR1184-1	unassigned_transcript_3892	n.*167G>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8A1	ENST00000610495.2	c.835C>G	p.Leu279Val	missense_variant	Exon 1 of 1	6	NM_012151.4	ENSP00000479624.1
F8	ENST00000360256.9	c.6429+8868G>C		intron_variant	Intron 22 of 25	1	NM_000132.4	ENSP00000353393.4
MIR1184-1	ENST00000408606.1	n.*151G>C		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.000123 AC: 5 AN: 40561 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00335

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000941 AC: 40 AN: 424941 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 123351

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

African (AFR) AF: 0.00 AC: 0 AN: 5482

American (AMR) AF: 0.00 AC: 0 AN: 17466

Ashkenazi Jewish (ASJ) AF: 0.00263 AC: 30 AN: 11428

East Asian (EAS) AF: 0.00 AC: 0 AN: 20658

South Asian (SAS) AF: 0.00 AC: 0 AN: 28747

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26784

Middle Eastern (MID) AF: 0.000652 AC: 1 AN: 1534

European-Non Finnish (NFE) AF: 0.0000137 AC: 4 AN: 291458

Other (OTH) AF: 0.000234 AC: 5 AN: 21384

⚠️ 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: 0.000123 AC: 5 AN: 40561 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 5849

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

African (AFR) AF: 0.00 AC: 0 AN: 2137

American (AMR) AF: 0.00 AC: 0 AN: 3300

Ashkenazi Jewish (ASJ) AF: 0.00335 AC: 5 AN: 1492

East Asian (EAS) AF: 0.00 AC: 0 AN: 954

South Asian (SAS) AF: 0.00 AC: 0 AN: 761

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 169

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 28475

Other (OTH) AF: 0.00 AC: 0 AN: 495

⚠️ 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: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.835C>G (p.L279V) alteration is located in exon 1 (coding exon 1) of the F8A1 gene. This alteration results from a C to G substitution at nucleotide position 835, causing the leucine (L) at amino acid position 279 to be replaced by a valine (V). 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	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.069	T
FATHMM_MKL	Benign	0.053	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.84
PrimateAI	Pathogenic	0.88	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.27
MutPred		0.62		Loss of helix (P = 0.1299);
MVP		0.13
ClinPred		0.37	T
GERP RS		1.4
Varity_R		0.069
gMVP		0.61
Mutation Taster		=97/3	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: rs1453070252; hg19: chrX-154115484;