2-26191048-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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:4

Conservation

PhyloP100: -1.73

Publications

15 publications found

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:27172): (GRB2 associated regulator of MAPK1 subtype 2)

GAREM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HADHA	NM_000182.5 link	c.*202G>A		3_prime_UTR_variant	Exon 20 of 20	ENST00000380649.8	NP_000173.2	P40939-1E9KL44
GAREM2	XM_011532567.4 link	c.1683+3733C>T		intron_variant	Intron 6 of 6		XP_011530869.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADHA	ENST00000380649.8 link	c.*202G>A		3_prime_UTR_variant	Exon 20 of 20	1	NM_000182.5	ENSP00000370023.3		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

African (AFR)

AF:

0.754

AC:

10840

AN:

14368

American (AMR)

AF:

0.783

AC:

22724

AN:

29010

Ashkenazi Jewish (ASJ)

AF:

0.677

AC:

10697

AN:

15802

East Asian (EAS)

AF:

0.876

AC:

27439

AN:

31318

South Asian (SAS)

AF:

0.768

AC:

39570

AN:

51528

European-Finnish (FIN)

AF:

0.723

AC:

22066

AN:

30502

Middle Eastern (MID)

AF:

0.744

AC:

1595

AN:

2144

European-Non Finnish (NFE)

AF:

0.788

AC:

228306

AN:

289720

Other (OTH)

AF:

0.775

AC:

21513

AN:

27760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

4562

9124

13687

18249

22811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.770

AC:

117059

AN:

152120

Hom.:

45038

Cov.:

AF XY:

0.766

AC XY:

56945

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.753

AC:

31257

AN:

41502

American (AMR)

AF:

0.781

AC:

11951

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.690

AC:

2391

AN:

3466

East Asian (EAS)

AF:

0.846

AC:

4368

AN:

5162

South Asian (SAS)

AF:

0.777

AC:

3746

AN:

4822

European-Finnish (FIN)

AF:

0.704

AC:

7452

AN:

10578

Middle Eastern (MID)

AF:

0.731

AC:

215

AN:

294

European-Non Finnish (NFE)

AF:

0.785

AC:

53393

AN:

67982

Other (OTH)

AF:

0.772

AC:

1627

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1420

2840

4260

5680

7100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.777

Hom.:

12762

Bravo

AF:

0.774

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mitochondrial trifunctional protein deficiency

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.48

(source)

DANN

Benign

0.68

PhyloP100

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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2-26191048-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over