NM_000132.4:c.*30G>A

Variant names:

• chrX-154837567-C-T
• rs376482768
• NM_000132.4:c.*30G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BS2_Supporting

The NM_000132.4(F8):​c.*30G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,184,721 control chromosomes in the GnomAD database, including 2 homozygotes. There are 79 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.00019 (2 hom. 72 hem.)
• Consequence: F8 NM_000132.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.870
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant X-154837567-C-T is Benign according to our data. Variant chrX-154837567-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 914336.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 7 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.*30G>A		3_prime_UTR_variant	Exon 26 of 26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.*30G>A		3_prime_UTR_variant	Exon 5 of 5		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.*30G>A		3_prime_UTR_variant	Exon 26 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10	c.*30G>A		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000327895.6
F8	ENST00000644698.1	c.*30G>A		3_prime_UTR_variant	Exon 6 of 6			ENSP00000495706.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 22 AN: 111530 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00642

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000378

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000566

Gnomad OTH AF: 0.000666

GnomAD2 exomes AF: 0.000392 AC: 56 AN: 142942 AF XY: 0.000506

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000436

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.000527

GnomAD4 exome AF: 0.000189 AC: 203 AN: 1073191 Hom.: 2 Cov.: 29 AF XY: 0.000207 AC XY: 72 AN XY: 348103

African (AFR) AF: 0.00 AC: 0 AN: 25928

American (AMR) AF: 0.0000319 AC: 1 AN: 31383

Ashkenazi Jewish (ASJ) AF: 0.00651 AC: 123 AN: 18888

East Asian (EAS) AF: 0.00 AC: 0 AN: 29094

South Asian (SAS) AF: 0.000390 AC: 20 AN: 51277

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3484

European-Non Finnish (NFE) AF: 0.0000458 AC: 38 AN: 828899

Other (OTH) AF: 0.000465 AC: 21 AN: 45178

GnomAD4 genome AF: 0.000197 AC: 22 AN: 111530 Hom.: 0 Cov.: 22 AF XY: 0.000208 AC XY: 7 AN XY: 33700

African (AFR) AF: 0.00 AC: 0 AN: 30614

American (AMR) AF: 0.00 AC: 0 AN: 10594

Ashkenazi Jewish (ASJ) AF: 0.00642 AC: 17 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.000378 AC: 1 AN: 2646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000566 AC: 3 AN: 53014

Other (OTH) AF: 0.000666 AC: 1 AN: 1501

Alfa AF: 0.00113 Hom.: 8

Bravo AF: 0.000268

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.19
DANN	Benign	0.45
PhyloP100		-0.87
Mutation Taster		=100/0	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: rs376482768; hg19: chrX-154065842; COSMIC: COSV100371876; COSMIC: COSV100371876;