X-155026934-TGGGAATGGAAACATCTGCCCCACGTGCCGGAAGCCAAGTGGTGGCGACAACTGCGCGCCACTCCGCGGCCTACCGCGCAGATCCTCTACGTGTGTCCTCGCGAGACAAGCTCACCGAAATGGCCGCGTCCAGTCAAGGTAAGGGCGGGCGCGCGCGCGGCCGGCGCCGCGGGGAGCCGCCTTCCTG-T

Position:

• chrX-155026934-TGGGAATGGAAACATCTGCCCCACGTGCCGGAAGCCAAGTGGTGGCGACAACTGCGCGCCACTCCGCGGCCTACCGCGCAGATCCTCTACGTGTGTCCTCGCGAGACAAGCTCACCGAAATGGCCGCGTCCAGTCAAGGTAAGGGCGGGCGCGCGCGCGGCCGGCGCCGCGGGGAGCCGCCTTCCTG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_023934.4(FUNDC2):​c.-2_133+51del variant causes a splice donor, splice donor 5th base, coding sequence, 5 prime UTR, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FUNDC2 NM_023934.4 splice_donor, splice_donor_5th_base, coding_sequence, 5_prime_UTR, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.36

Genes affected

FUNDC2 (HGNC:24925): (FUN14 domain containing 2) Predicted to be involved in autophagy of mitochondrion. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.3982456 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-155026934-TGGGAATGGAAACATCTGCCCCACGTGCCGGAAGCCAAGTGGTGGCGACAACTGCGCGCCACTCCGCGGCCTACCGCGCAGATCCTCTACGTGTGTCCTCGCGAGACAAGCTCACCGAAATGGCCGCGTCCAGTCAAGGTAAGGGCGGGCGCGCGCGCGGCCGGCGCCGCGGGGAGCCGCCTTCCTG-T is Pathogenic according to our data. Variant chrX-155026934-TGGGAATGGAAACATCTGCCCCACGTGCCGGAAGCCAAGTGGTGGCGACAACTGCGCGCCACTCCGCGGCCTACCGCGCAGATCCTCTACGTGTGTCCTCGCGAGACAAGCTCACCGAAATGGCCGCGTCCAGTCAAGGTAAGGGCGGGCGCGCGCGCGGCCGGCGCCGCGGGGAGCCGCCTTCCTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 973793.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FUNDC2	NM_023934.4	c.-2_133+51del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	1/5	ENST00000369498.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FUNDC2	ENST00000369498.8	c.-2_133+51del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	1/5	1	NM_023934.4	P1
F8	ENST00000423959.5			5_prime_UTR_variant	1/6	3
FUNDC2	ENST00000475165.5	n.242+257_242+442del		intron_variant, non_coding_transcript_variant		3
FUNDC2	ENST00000484175.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Jun 01, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2073793798; hg19: chrX-154255209;