rs59947000

Variant names:

• chr2-26254257-G-GACT
• rs3839049
• NM_000183.3:c.5_7dupCTA

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_000183.3(HADHB):​c.5_7dupCTA​(p.Thr2dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58895 hom., cov: 0)
  • Exomes 𝑓: 0.88 (470684 hom.)
• Consequence: HADHB NM_000183.3 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.901
• Publications: 8 publications found

Genes affected

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]

HADHB Gene-Disease associations (from GenCC):

• mitochondrial trifunctional protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000183.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-26254257-G-GACT is Benign according to our data. Variant chr2-26254257-G-GACT is described in ClinVar as Benign. ClinVar VariationId is 92600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADHB	NM_000183.3	c.5_7dupCTA	p.Thr2dup	disruptive_inframe_insertion	Exon 2 of 16	ENST00000317799.10	NP_000174.1
HADHB	NM_001281512.2	c.5_7dupCTA	p.Thr2dup	disruptive_inframe_insertion	Exon 2 of 15		NP_001268441.1
HADHB	XM_011532803.2	c.5_7dupCTA	p.Thr2dup	disruptive_inframe_insertion	Exon 2 of 16		XP_011531105.1
HADHB	NM_001281513.2	c.-145_-143dupCTA		5_prime_UTR_variant	Exon 2 of 17		NP_001268442.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADHB	ENST00000317799.10	c.5_7dupCTA	p.Thr2dup	disruptive_inframe_insertion	Exon 2 of 16	1	NM_000183.3	ENSP00000325136.5

Frequencies

GnomAD3 genomes AF: 0.868 AC: 131734 AN: 151840 Hom.: 58846 Cov.: 0

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.817

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.933

Gnomad OTH AF: 0.861

GnomAD2 exomes AF: 0.819 AC: 205645 AN: 250998 AF XY: 0.834

Gnomad AFR exome AF: 0.877

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.178

Gnomad FIN exome AF: 0.938

Gnomad NFE exome AF: 0.936

Gnomad OTH exome AF: 0.870

GnomAD4 exome AF: 0.877 AC: 1039351 AN: 1184466 Hom.: 470684 Cov.: 19 AF XY: 0.880 AC XY: 529990 AN XY: 602496

African (AFR) AF: 0.864 AC: 24550 AN: 28408

American (AMR) AF: 0.634 AC: 28187 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.901 AC: 22005 AN: 24412

East Asian (EAS) AF: 0.161 AC: 6299 AN: 39162

South Asian (SAS) AF: 0.843 AC: 67905 AN: 80556

European-Finnish (FIN) AF: 0.940 AC: 50055 AN: 53250

Middle Eastern (MID) AF: 0.922 AC: 3817 AN: 4140

European-Non Finnish (NFE) AF: 0.923 AC: 792294 AN: 858456

Other (OTH) AF: 0.857 AC: 44239 AN: 51638

GnomAD4 genome AF: 0.868 AC: 131841 AN: 151960 Hom.: 58895 Cov.: 0 AF XY: 0.860 AC XY: 63877 AN XY: 74258

African (AFR) AF: 0.876 AC: 36294 AN: 41422

American (AMR) AF: 0.738 AC: 11257 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 3129 AN: 3464

East Asian (EAS) AF: 0.184 AC: 950 AN: 5168

South Asian (SAS) AF: 0.817 AC: 3940 AN: 4822

European-Finnish (FIN) AF: 0.938 AC: 9908 AN: 10564

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 0.933 AC: 63434 AN: 67956

Other (OTH) AF: 0.860 AC: 1812 AN: 2106

Alfa AF: 0.897 Hom.: 40930

Bravo AF: 0.847

Asia WGS AF: 0.584 AC: 2031 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 02, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 83% of total chromosomes in ExAC -

Aug 27, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in HADHB panel(s). -

Mitochondrial trifunctional protein deficiency Benign:3

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Other:1

-

Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3839049; hg19: chr2-26477125; COSMIC: COSV58544319;