rs142348718

chr2-26192329-G-Achr2-26192329-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000182.5(HADHA):c.1981C>T(p.Leu661=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 1,587,454 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L661L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (43 hom.)
• Consequence: HADHA NM_000182.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.703

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]

GAREM2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-26192329-G-A is Benign according to our data. Variant chr2-26192329-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26192329-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.703 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00445 (678/152262) while in subpopulation NFE AF= 0.00786 (535/68036). AF 95% confidence interval is 0.00731. There are 3 homozygotes in gnomad4. There are 287 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HADHA	NM_000182.5	c.1981C>T	p.Leu661=	synonymous_variant	18/20	ENST00000380649.8
GAREM2	XM_011532567.4	c.1683+5014G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADHA	ENST00000380649.8	c.1981C>T	p.Leu661=	synonymous_variant	18/20	1	NM_000182.5	P1

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 678 AN: 152150 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00788

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00419 AC: 1053 AN: 251474 Hom.: 6 AF XY: 0.00420 AC XY: 571 AN XY: 135908

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00717

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00684 AC: 9823 AN: 1435192 Hom.: 43 Cov.: 28 AF XY: 0.00660 AC XY: 4723 AN XY: 715802

Gnomad4 AFR exome AF: 0.00100

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.000732

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000443

Gnomad4 FIN exome AF: 0.00193

Gnomad4 NFE exome AF: 0.00839

Gnomad4 OTH exome AF: 0.00546

GnomAD4 genome AF: 0.00445 AC: 678 AN: 152262 Hom.: 3 Cov.: 32 AF XY: 0.00386 AC XY: 287 AN XY: 74426

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00786

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00526 Hom.: 1

Bravo AF: 0.00433

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00758

EpiControl AF: 0.00753

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2017	Variant summary: The HADHA c.1981C>T (p.Leu661Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 517/121374 control chromosomes (including 4 homozygotes) at a frequency of 0.0042596, which is approximately 2.2 times the estimated maximal expected allele frequency of a pathogenic HADHA variant (0.0019365), suggesting this variant is likely a benign polymorphism. It is more common in European (Non-Finnish) subpopulation with allele frequency of 0.006 (441/66716) including all reported homozygotes. One clinical diagnostic laboratory in ClinVar has classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	HADHA: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 18, 2020	- -

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Mitochondrial trifunctional protein deficiency Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.83
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

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: rs142348718; hg19: chr2-26415198;