chr2-26279189-C-T

Position:

• chr2-26279189-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000183.3(HADHB):​c.685C>T​(p.Arg229*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000821 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: HADHB NM_000183.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.61

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]

HADHB (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 2-26279189-C-T is Pathogenic according to our data. Variant chr2-26279189-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 579455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADHB	NM_000183.3	c.685C>T	p.Arg229*	stop_gained	9/16	ENST00000317799.10	NP_000174.1
HADHB	NM_001281512.2	c.640C>T	p.Arg214*	stop_gained	8/15		NP_001268441.1
HADHB	NM_001281513.2	c.619C>T	p.Arg207*	stop_gained	10/17		NP_001268442.1
HADHB	XM_011532803.2	c.685C>T	p.Arg229*	stop_gained	9/16		XP_011531105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADHB	ENST00000317799.10	c.685C>T	p.Arg229*	stop_gained	9/16	1	NM_000183.3	ENSP00000325136.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251332 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461370 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial trifunctional protein deficiency 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 17, 2022

- -

Mitochondrial trifunctional protein deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 07, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 579455). This premature translational stop signal has been observed in individual(s) with a fatty acid oxidation disorder (PMID: 12754706). This variant is present in population databases (rs759136382, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg229*) in the HADHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HADHB are known to be pathogenic (PMID: 9259266, 12754706). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.77
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs759136382; hg19: chr2-26502057; COSMIC: COSV58545179; COSMIC: COSV58545179;