NM_012151.4:c.23T>G

Variant names:

• chrX-154886397-T-G
• NM_012151.4:c.23T>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.23T>G​(p.Leu8Arg) 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: not found (cov: 1)
• Consequence: F8A1 NM_012151.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.200
• 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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13204771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8A1	NM_012151.4	c.23T>G	p.Leu8Arg	missense_variant	Exon 1 of 1	ENST00000610495.2	NP_036283.2
F8	NM_000132.4	c.6429+9680A>C		intron_variant	Intron 22 of 25	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.-240A>C		upstream_gene_variant			NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8A1	ENST00000610495.2	c.23T>G	p.Leu8Arg	missense_variant	Exon 1 of 1	6	NM_012151.4	ENSP00000479624.1
F8	ENST00000360256.9	c.6429+9680A>C		intron_variant	Intron 22 of 25	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10	c.-240A>C		upstream_gene_variant		1		ENSP00000327895.6

Frequencies

GnomAD3 genomes Cov.: 1

GnomAD4 exome Cov.: 4

GnomAD4 genome Cov.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23T>G (p.L8R) alteration is located in exon 1 (coding exon 1) of the F8A1 gene. This alteration results from a T to G substitution at nucleotide position 23, causing the leucine (L) at amino acid position 8 to be replaced by an arginine (R). 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	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.59
DEOGEN2	Benign	0.017	T
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.20
PrimateAI	Pathogenic	0.85	D
Sift4G	Benign	0.39	T
Polyphen		0.87	P
Vest4		0.18
MutPred		0.27		Gain of methylation at L8 (P = 7e-04);
MVP		0.15
ClinPred		0.15	T
GERP RS		1.5
PromoterAI		-0.089	Neutral
Varity_R		0.13
gMVP		0.44
Mutation Taster		=99/1	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

hg19: chrX-154114672;