Genetic Variant FUNDC2:p.Met1_Gly45del (chrX-155026934-TGGGAATGGAAACATCTGCCCCACGTGCCGGAAGCCAAGTGGTGGCGACAACTGCGCGCCACTCCGCGGCCTACCGCGCAGATCCTCTACGTGTGTCCTCGCGAGACAAGCTCACCGAAATGGCCGCGTCCAGTCAAGGTAAGGGCGGGCGCGCGCGCGGCCGGCGCCGCGGGGAGCCGCCTTCCTG-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4PP5

The NM_023934.4(FUNDC2):c.-2_133+51del(p.Met1_Gly45del) variant causes a start lost, conservative inframe deletion, splice region 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 start_lost, conservative_inframe_deletion, splice_region

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.36

Variant links:

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]

FUNDC2 links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_023934.4.

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 rank	MANE	Protein	UniProt
FUNDC2	NM_023934.4 link	c.-2_133+51del	p.Met1_Gly45del	start_lost, conservative_inframe_deletion, splice_region_variant	Exon 1 of 5	ENST00000369498.8	NP_076423.2	Q9BWH2
FUNDC2	NM_023934.4 link	c.-2_133+51del		splice_donor_variant, splice_region_variant, 5_prime_UTR_variant, intron_variant	Exon 1 of 5	ENST00000369498.8	NP_076423.2	Q9BWH2
F8		n.155027120_155026935del		bidirectional_gene_fusion

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUNDC2	ENST00000369498.8 link	c.-4_133+49del	p.Met1fs	frameshift_variant, start_lost, splice_region_variant	Exon 1 of 5	1	NM_023934.4	ENSP00000358510.3		Q9BWH2
FUNDC2	ENST00000369498 link	c.-4_133+49del		splice_donor_variant, splice_region_variant, 5_prime_UTR_variant, intron_variant	Exon 1 of 5	1	NM_023934.4	ENSP00000358510.3		Q9BWH2

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:1

Jun 01, 2019

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.