rs142348718

Variant names:

• chr2-26192329-G-A
• rs142348718
• NM_000182.5:c.1981C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26192329-G-A
• chr2-26192329-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000182.5(HADHA):​c.1981C>T​(p.Leu661Leu) 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:11
• Conservation: PhyloP100: -0.703
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 92595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000182.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHA	NM_000182.5	MANE Select	c.1981C>T	p.Leu661Leu	synonymous	Exon 18 of 20	NP_000173.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHA	ENST00000380649.8	TSL:1 MANE Select	c.1981C>T	p.Leu661Leu	synonymous	Exon 18 of 20	ENSP00000370023.3
	HADHA	ENST00000492433.2	TSL:2	c.1981C>T	p.Leu661Leu	synonymous	Exon 18 of 19	ENSP00000438039.2
	HADHA	ENST00000645274.1		c.1876C>T	p.Leu626Leu	synonymous	Exon 17 of 19	ENSP00000493996.1

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

GnomAD2 exomes AF: 0.00419 AC: 1053 AN: 251474 AF XY: 0.00420

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 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

African (AFR) AF: 0.00100 AC: 33 AN: 32930

American (AMR) AF: 0.00387 AC: 173 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000732 AC: 19 AN: 25974

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39598

South Asian (SAS) AF: 0.000443 AC: 38 AN: 85710

European-Finnish (FIN) AF: 0.00193 AC: 103 AN: 53410

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5700

European-Non Finnish (NFE) AF: 0.00839 AC: 9125 AN: 1087646

Other (OTH) AF: 0.00546 AC: 325 AN: 59520

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

African (AFR) AF: 0.00137 AC: 57 AN: 41542

American (AMR) AF: 0.00379 AC: 58 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10586

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00786 AC: 535 AN: 68036

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Apr 10, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HADHA: BP4, BP7, BS2

Nov 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 16, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Aug 30, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 18, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 11, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 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 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.83
DANN	Benign	0.83
PhyloP100		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs142348718; hg19: chr2-26415198;