rs121913134

Variant names:

• chr2-26285513-G-A
• rs121913134
• NM_000183.3:c.1331G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000183.3(HADHB):​c.1331G>A​(p.Arg444Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HADHB NM_000183.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.89

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 2-26285513-G-A is Pathogenic according to our data. Variant chr2-26285513-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14847.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADHB	NM_000183.3	c.1331G>A	p.Arg444Lys	missense_variant	Exon 15 of 16	ENST00000317799.10	NP_000174.1
HADHB	NM_001281512.2	c.1286G>A	p.Arg429Lys	missense_variant	Exon 14 of 15		NP_001268441.1
HADHB	NM_001281513.2	c.1265G>A	p.Arg422Lys	missense_variant	Exon 16 of 17		NP_001268442.1
HADHB	XM_011532803.2	c.1331G>A	p.Arg444Lys	missense_variant	Exon 15 of 16		XP_011531105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADHB	ENST00000317799.10	c.1331G>A	p.Arg444Lys	missense_variant	Exon 15 of 16	1	NM_000183.3	ENSP00000325136.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial trifunctional protein deficiency 2 Pathogenic:1

Dec 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;D;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.8	.;L;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Pathogenic	0.88
Sift	Benign	0.075	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.81
MutPred		0.86		.;Loss of methylation at R444 (P = 0.0318);.;.;
MVP		0.99
MPC		0.62
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.92

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: rs121913134; hg19: chr2-26508381;