NM_000183.3:c.397A>G

Variant names:

• chr2-26277115-A-G
• rs371159065
• NM_000183.3:c.397A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP2 PP3 PP5

The NM_000183.3(HADHB):​c.397A>G​(p.Thr133Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,607,024 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T133T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: HADHB NM_000183.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:4
• Conservation: PhyloP100: 9.27
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000183.3
• 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, 0.836
• PP5: Variant 2-26277115-A-G is Pathogenic according to our data. Variant chr2-26277115-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235337.

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.397A>G	p.Thr133Ala	missense	Exon 7 of 16	NP_000174.1	P55084-1
	HADHB	NM_001281512.2		c.352A>G	p.Thr118Ala	missense	Exon 6 of 15	NP_001268441.1	F5GZQ3
	HADHB	NM_001281513.2		c.331A>G	p.Thr111Ala	missense	Exon 8 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.397A>G	p.Thr133Ala	missense	Exon 7 of 16	ENSP00000325136.5	P55084-1
	HADHB	ENST00000942431.1		c.481A>G	p.Thr161Ala	missense	Exon 8 of 17	ENSP00000612490.1
	HADHB	ENST00000942426.1		c.427A>G	p.Thr143Ala	missense	Exon 7 of 16	ENSP00000612485.1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 151942 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000111 AC: 28 AN: 251430 AF XY: 0.000110

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000199 AC: 289 AN: 1455082 Hom.: 1 Cov.: 28 AF XY: 0.000197 AC XY: 143 AN XY: 724400

African (AFR) AF: 0.0000599 AC: 2 AN: 33370

American (AMR) AF: 0.000201 AC: 9 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.000234 AC: 259 AN: 1105966

Other (OTH) AF: 0.000299 AC: 18 AN: 60190

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 151942 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74216

African (AFR) AF: 0.00 AC: 0 AN: 41342

American (AMR) AF: 0.0000656 AC: 1 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68004

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000350 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Mitochondrial trifunctional protein deficiency 2 (3)
1	2	-	not provided (3)
1	1	-	Mitochondrial trifunctional protein deficiency (2)
1	-	-	Mitochondrial trifunctional protein deficiency 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.033	D
Polyphen		0.79	P
Vest4		0.93
MVP		0.98
MPC		0.56
ClinPred		0.25	T
GERP RS		5.9
Varity_R		0.81
gMVP		0.89
Mutation Taster		=3/97	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: rs371159065; hg19: chr2-26499983;