rs71441018

Positions:

• chr2-26230216-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000182.5(HADHA):​c.652G>C​(p.Val218Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000592 in 1,610,922 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V218V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: HADHA NM_000182.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 4.79

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03135246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HADHA	NM_000182.5	c.652G>C	p.Val218Leu	missense_variant	7/20	ENST00000380649.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADHA	ENST00000380649.8	c.652G>C	p.Val218Leu	missense_variant	7/20	1	NM_000182.5	P1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000851 AC: 214 AN: 251488 Hom.: 0 AF XY: 0.000956 AC XY: 130 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000596 AC: 870 AN: 1458608 Hom.: 1 Cov.: 30 AF XY: 0.000672 AC XY: 488 AN XY: 725896

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00391

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000419

Gnomad4 OTH exome AF: 0.000913

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74484

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000790 Hom.: 0

Bravo AF: 0.000601

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000865 AC: 105

EpiCase AF: 0.00115

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported with a high frequency of heterozygous individuals in the Silesian region of Poland in published literature (Nedoszytko et al., 2017); This variant is associated with the following publications: (PMID: 29095929) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	- -

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Mitochondrial trifunctional protein deficiency 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

- -

Mitochondrial trifunctional protein deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	0.0021	T
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.6	D;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0040	D;.;.
Sift4G	Uncertain	0.0060	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.74
MVP		0.66
MPC		0.65
ClinPred		0.14	T
GERP RS		5.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.94
gMVP		0.91

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: rs71441018; hg19: chr2-26453084;