rs137852773

Positions:

• chr2-26214516-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000182.5(HADHA):​c.845T>A​(p.Val282Asp) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HADHA NM_000182.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.46

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 2-26214516-A-T is Pathogenic according to our data. Variant chr2-26214516-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 8735.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADHA	NM_000182.5	c.845T>A	p.Val282Asp	missense_variant	9/20	ENST00000380649.8	NP_000173.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADHA	ENST00000380649.8	c.845T>A	p.Val282Asp	missense_variant	9/20	1	NM_000182.5	ENSP00000370023	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial trifunctional protein deficiency 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.053	D
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.8	D;.;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;.;.
Sift4G	Pathogenic	0.0010	D;.;.
Polyphen		0.92	P;.;.
Vest4		0.88
MutPred		0.85		Loss of MoRF binding (P = 0.0186);Loss of MoRF binding (P = 0.0186);.;
MVP		0.92
MPC		0.88
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.89

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: rs137852773; hg19: chr2-26437385;