2-26279190-G-T

Variant names:

• chr2-26279190-G-T
• rs375654005
• NM_000183.3:c.686G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000183.3(HADHB):​c.686G>T​(p.Arg229Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R229Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HADHB NM_000183.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.53
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial trifunctional protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26279190-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 429516.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.64924 (below the threshold of 3.09). Trascript score misZ: 0.82597 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial trifunctional protein deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000183.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHB	NM_000183.3	MANE Select	c.686G>T	p.Arg229Leu	missense	Exon 9 of 16	NP_000174.1	P55084-1
	HADHB	NM_001281512.2		c.641G>T	p.Arg214Leu	missense	Exon 8 of 15	NP_001268441.1	F5GZQ3
	HADHB	NM_001281513.2		c.620G>T	p.Arg207Leu	missense	Exon 10 of 17	NP_001268442.1	P55084-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHB	ENST00000317799.10	TSL:1 MANE Select	c.686G>T	p.Arg229Leu	missense	Exon 9 of 16	ENSP00000325136.5	P55084-1
	HADHB	ENST00000942431.1		c.770G>T	p.Arg257Leu	missense	Exon 10 of 17	ENSP00000612490.1
	HADHB	ENST00000942426.1		c.716G>T	p.Arg239Leu	missense	Exon 9 of 16	ENSP00000612485.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.0	L
PhyloP100		9.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.11	T
Polyphen		0.70	P
Vest4		0.88
MutPred		0.65		Loss of disorder (P = 0.0418)
MVP		0.98
MPC		0.66
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.84
Mutation Taster		=0/100	disease causing

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: rs375654005; hg19: chr2-26502058;