2-26244479-C-A

Position:

• chr2-26244479-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000182.5(HADHA):​c.67+51G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,542,746 control chromosomes in the GnomAD database, including 33,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2767 hom., cov: 33)
  • Exomes 𝑓: 0.20 (30423 hom.)
• Consequence: HADHA NM_000182.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.105

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]

HADHB (HGNC:4803): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta) This gene encodes the beta 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 beta subunit catalyzing the 3-ketoacyl-CoA thiolase activity. The encoded protein can also bind RNA and decreases the stability of some mRNAs. 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. Mutations in this gene result in trifunctional protein deficiency. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-26244479-C-A is Benign according to our data. Variant chr2-26244479-C-A is described in ClinVar as [Benign]. Clinvar id is 676134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HADHA	NM_000182.5	c.67+51G>T		intron_variant		ENST00000380649.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADHA	ENST00000380649.8	c.67+51G>T		intron_variant		1	NM_000182.5	P1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27040 AN: 152106 Hom.: 2763 Cov.: 33

Gnomad AFR AF: 0.0670

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.215 AC: 33212 AN: 154134 Hom.: 3776 AF XY: 0.216 AC XY: 17754 AN XY: 82102

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.154

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.204 AC: 284192 AN: 1390522 Hom.: 30423 Cov.: 29 AF XY: 0.205 AC XY: 140960 AN XY: 686644

Gnomad4 AFR exome AF: 0.0612

Gnomad4 AMR exome AF: 0.204

Gnomad4 ASJ exome AF: 0.322

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.281

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.207

GnomAD4 genome AF: 0.178 AC: 27061 AN: 152224 Hom.: 2767 Cov.: 33 AF XY: 0.183 AC XY: 13585 AN XY: 74428

Gnomad4 AFR AF: 0.0670

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.154

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.195

Alfa AF: 0.211 Hom.: 643

Bravo AF: 0.165

Asia WGS AF: 0.236 AC: 821 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.4
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs62128457; hg19: chr2-26467347;