2-26191048-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000182.5(HADHA):c.*202G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.779 in 644,272 control chromosomes in the GnomAD database, including 195,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45038 hom., cov: 32)

Exomes 𝑓: 0.78 ( 150945 hom. )

Consequence

HADHA
NM_000182.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.73

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:

GAREM2 (HGNC:):

GAREM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-26191048-C-T is Benign according to our data. Variant chr2-26191048-C-T is described in ClinVar as [Benign]. Clinvar id is 335372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HADHA	NM_000182.5 linkuse as main transcript	c.*202G>A		3_prime_UTR_variant	20/20	ENST00000380649.8
GAREM2	XM_011532567.4 linkuse as main transcript	c.1683+3733C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADHA	ENST00000380649.8 linkuse as main transcript	c.*202G>A		3_prime_UTR_variant	20/20	1	NM_000182.5	P1	P40939-1

Frequencies

GnomAD3 genomes

AF:

0.770

AC:

116987

AN:

152002

Hom.:

45019

Cov.:

show subpopulations

Gnomad AFR

AF:

0.753

Gnomad AMI

AF:

0.724

Gnomad AMR

AF:

0.781

Gnomad ASJ

AF:

0.690

Gnomad EAS

AF:

0.847

Gnomad SAS

AF:

0.777

Gnomad FIN

AF:

0.704

Gnomad MID

AF:

0.712

Gnomad NFE

AF:

0.785

Gnomad OTH

AF:

0.774

GnomAD4 exome

AF:

0.782

AC:

384750

AN:

492152

Hom.:

150945

Cov.:

AF XY:

0.781

AC XY:

204154

AN XY:

261286

show subpopulations

Gnomad4 AFR exome

AF:

0.754

Gnomad4 AMR exome

AF:

0.783

Gnomad4 ASJ exome

AF:

0.677

Gnomad4 EAS exome

AF:

0.876

Gnomad4 SAS exome

AF:

0.768

Gnomad4 FIN exome

AF:

0.723

Gnomad4 NFE exome

AF:

0.788

Gnomad4 OTH exome

AF:

0.775

GnomAD4 genome

AF:

0.770

AC:

117059

AN:

152120

Hom.:

45038

Cov.:

AF XY:

0.766

AC XY:

56945

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.753

Gnomad4 AMR

AF:

0.781

Gnomad4 ASJ

AF:

0.690

Gnomad4 EAS

AF:

0.846

Gnomad4 SAS

AF:

0.777

Gnomad4 FIN

AF:

0.704

Gnomad4 NFE

AF:

0.785

Gnomad4 OTH

AF:

0.772

Alfa

AF:

0.774

Hom.:

11409

Bravo

AF:

0.774

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

- -

Mitochondrial trifunctional protein deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

Cadd

Benign

0.48

Dann

Benign

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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