2-26230279-C-T

Variant names:

• chr2-26230279-C-T
• rs116320983
• NM_000182.5:c.589G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000182.5(HADHA):​c.589G>A​(p.Ala197Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A197S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HADHA NM_000182.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.70
• Publications: 0 publications found

Genes affected

HADHA (HGNC:4801): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) This gene encodes the alpha 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 alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. Mutations in this gene result in trifunctional protein deficiency or LCHAD deficiency. 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. [provided by RefSeq, Jul 2008]

HADHA Gene-Disease associations (from GenCC):

• long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• mitochondrial trifunctional protein deficiency

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000182.5. 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
	HADHA	NM_000182.5	MANE Select	c.589G>A	p.Ala197Thr	missense	Exon 7 of 20	NP_000173.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHA	ENST00000380649.8	TSL:1 MANE Select	c.589G>A	p.Ala197Thr	missense	Exon 7 of 20	ENSP00000370023.3	P40939-1
	HADHA	ENST00000942149.1		c.589G>A	p.Ala197Thr	missense	Exon 7 of 21	ENSP00000612208.1
	HADHA	ENST00000942146.1		c.589G>A	p.Ala197Thr	missense	Exon 7 of 20	ENSP00000612205.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251470 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459724 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726268

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110102

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.80
Sift	Benign	0.047	D
Sift4G	Uncertain	0.021	D
Polyphen		0.93	P
Vest4		0.93
MutPred		0.86		Gain of phosphorylation at A197 (P = 0.0602)
MVP		0.91
MPC		0.76
ClinPred		0.95	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.82
gMVP		0.97
Mutation Taster		=26/74	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: rs116320983; hg19: chr2-26453147;