chr2-26214447-A-T

Position:

chr2-26214447-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000380649.8(HADHA):c.914T>A(p.Ile305Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,295,830 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I305T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

HADHA
ENST00000380649.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 8.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-26214447-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 453019.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 2-26214447-A-T is Pathogenic according to our data. Variant chr2-26214447-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8736.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
HADHA	NM_000182.5 linkuse as main transcript	c.914T>A	p.Ile305Asn	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 linkuse as main transcript	c.914T>A	p.Ile305Asn	missense_variant	9/20	1	NM_000182.5	ENSP00000370023	P1	P40939-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251006

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135636

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000262

AC:

AN:

1295830

Hom.:

Cov.:

AF XY:

0.0000337

AC XY:

AN XY:

653692

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000343

Gnomad4 OTH exome

AF:

0.0000183

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 03, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2023	- -

Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 305 of the HADHA protein (p.Ile305Asn). This variant is present in population databases (rs137852774, gnomAD 0.002%). This missense change has been observed in individual(s) with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and/or MTP deficiency (PMID: 9739053, 21549624, 26109258, 29268767). ClinVar contains an entry for this variant (Variation ID: 8736). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HADHA protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial trifunctional protein deficiency 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 1998

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2021

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9739053, 2019931, 21549624, 26109258, 29268767, 33610471, 32253025, 31589614) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

D;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

4.3

H;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.6

D;.;.

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;.;.

Sift4G

Pathogenic

0.0010

D;.;.

Polyphen

0.99

D;.;.

Vest4

0.99

MutPred

0.89

Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);.;

MVP

0.92

MPC

1.1

ClinPred

1.0

GERP RS

5.4

Varity_R

0.90

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over