rs987203346

Positions:

• chr2-26279198-G-A
• chr2-26279198-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000183.3(HADHB):​c.694G>A​(p.Ala232Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: HADHB NM_000183.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.53

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADHB	NM_000183.3	c.694G>A	p.Ala232Thr	missense_variant	9/16	ENST00000317799.10	NP_000174.1
HADHB	NM_001281512.2	c.649G>A	p.Ala217Thr	missense_variant	8/15		NP_001268441.1
HADHB	NM_001281513.2	c.628G>A	p.Ala210Thr	missense_variant	10/17		NP_001268442.1
HADHB	XM_011532803.2	c.694G>A	p.Ala232Thr	missense_variant	9/16		XP_011531105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADHB	ENST00000317799.10	c.694G>A	p.Ala232Thr	missense_variant	9/16	1	NM_000183.3	ENSP00000325136.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251342 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1461188 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial trifunctional protein deficiency Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Medical Genetics, University Hospital of North Norway	Jul 18, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.91	.;L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.51
Sift	Benign	0.084	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.77	P;P;.
Vest4		0.65
MutPred		0.39		.;Gain of sheet (P = 0.0221);.;
MVP		0.93
MPC		0.26
ClinPred		0.87	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs987203346; hg19: chr2-26502066;