2-26277074-C-CT

Position:

• chr2-26277074-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000317799.10(HADHB):​c.357dup​(p.Ala120CysfsTer8) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HADHB ENST00000317799.10 frameshift, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.240

Genes affected

HADHB (HGNC:4803): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta) This gene encodes the beta subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the beta subunit catalyzing the 3-ketoacyl-CoA thiolase activity. The encoded protein can also bind RNA and decreases the stability of some mRNAs. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. Mutations in this gene result in trifunctional protein deficiency. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26277074-C-CT is Pathogenic according to our data. Variant chr2-26277074-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 253049.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADHB	NM_000183.3	c.357dup	p.Ala120CysfsTer8	frameshift_variant, splice_region_variant	7/16	ENST00000317799.10	NP_000174.1
HADHB	NM_001281512.2	c.312dup	p.Ala105CysfsTer8	frameshift_variant, splice_region_variant	6/15		NP_001268441.1
HADHB	NM_001281513.2	c.291dup	p.Ala98CysfsTer8	frameshift_variant, splice_region_variant	8/17		NP_001268442.1
HADHB	XM_011532803.2	c.357dup	p.Ala120CysfsTer8	frameshift_variant, splice_region_variant	7/16		XP_011531105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADHB	ENST00000317799.10	c.357dup	p.Ala120CysfsTer8	frameshift_variant, splice_region_variant	7/16	1	NM_000183.3	ENSP00000325136	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial trifunctional protein deficiency 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs886037844; hg19: chr2-26499942;