rs3839049

Positions:

• chr2-26254257-G-GACT

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_000183.3(HADHB):​c.5_7dup​(p.Thr2dup) variant causes a 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 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.901

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
HADHB	NM_000183.3	c.5_7dup	p.Thr2dup	inframe_insertion	2/16	ENST00000317799.10
HADHB	NM_001281512.2	c.5_7dup	p.Thr2dup	inframe_insertion	2/15
HADHB	XM_011532803.2	c.5_7dup	p.Thr2dup	inframe_insertion	2/16
HADHB	NM_001281513.2	c.-145_-143dup		5_prime_UTR_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADHB	ENST00000317799.10	c.5_7dup	p.Thr2dup	inframe_insertion	2/16	1	NM_000183.3	P1

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

GnomAD3 exomes AF: 0.819 AC: 205645 AN: 250998 Hom.: 90048 AF XY: 0.834 AC XY: 113224 AN XY: 135752

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 SAS exome AF: 0.846

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

Gnomad4 AFR exome AF: 0.864

Gnomad4 AMR exome AF: 0.634

Gnomad4 ASJ exome AF: 0.901

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.843

Gnomad4 FIN exome AF: 0.940

Gnomad4 NFE exome AF: 0.923

Gnomad4 OTH exome AF: 0.857

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

Gnomad4 AFR AF: 0.876

Gnomad4 AMR AF: 0.738

Gnomad4 ASJ AF: 0.903

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.817

Gnomad4 FIN AF: 0.938

Gnomad4 NFE AF: 0.933

Gnomad4 OTH AF: 0.860

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2013	The variant is found in HADHB panel(s). -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2013	- -

Mitochondrial trifunctional protein deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Other:1

not provided, no classification provided

literature only

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

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3839049; hg19: chr2-26477125;