NM_000183.3:c.182G>A

Variant names:

• chr2-26263452-G-A
• rs121913132
• NM_000183.3:c.182G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000183.3(HADHB):​c.182G>A​(p.Arg61His) variant causes a missense change. The variant allele was found at a frequency of 0.0000503 in 1,610,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R61C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: HADHB NM_000183.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.03
• Publications: 9 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), ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26263451-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.64924 (below the threshold of 3.09). Trascript score misZ: 0.82597 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial trifunctional protein deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 2-26263452-G-A is Pathogenic according to our data. Variant chr2-26263452-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000183.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHB	NM_000183.3	MANE Select	c.182G>A	p.Arg61His	missense	Exon 4 of 16	NP_000174.1	P55084-1
	HADHB	NM_001281512.2		c.182G>A	p.Arg61His	missense	Exon 4 of 15	NP_001268441.1	F5GZQ3
	HADHB	NM_001281513.2		c.116G>A	p.Arg39His	missense	Exon 5 of 17	NP_001268442.1	P55084-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHB	ENST00000317799.10	TSL:1 MANE Select	c.182G>A	p.Arg61His	missense	Exon 4 of 16	ENSP00000325136.5	P55084-1
	HADHB	ENST00000942431.1		c.266G>A	p.Arg89His	missense	Exon 5 of 17	ENSP00000612490.1
	HADHB	ENST00000942426.1		c.212G>A	p.Arg71His	missense	Exon 4 of 16	ENSP00000612485.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000636 AC: 16 AN: 251492 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000500 AC: 73 AN: 1458552 Hom.: 0 Cov.: 30 AF XY: 0.0000579 AC XY: 42 AN XY: 725746

African (AFR) AF: 0.0000598 AC: 2 AN: 33418

American (AMR) AF: 0.000112 AC: 5 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39672

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000487 AC: 54 AN: 1109064

Other (OTH) AF: 0.0000498 AC: 3 AN: 60248

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152100 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74304

African (AFR) AF: 0.0000242 AC: 1 AN: 41406

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000289 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Mitochondrial trifunctional protein deficiency 2 (3)
2	-	-	Mitochondrial trifunctional protein deficiency (2)
1	-	-	Mitochondrial trifunctional protein deficiency 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		7.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MVP		1.0
MPC		0.68
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs121913132; hg19: chr2-26486320;