rs375654005

Variant names:

• chr2-26279190-G-A
• rs375654005
• NM_000183.3:c.686G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-26279190-G-A
• chr2-26279190-G-C
• chr2-26279190-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000183.3(HADHB):​c.686G>A​(p.Arg229Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,650 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R229L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HADHB NM_000183.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 9.53
• Publications: 5 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.897
• PP5: Variant 2-26279190-G-A is Pathogenic according to our data. Variant chr2-26279190-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429516.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADHB	NM_000183.3	c.686G>A	p.Arg229Gln	missense_variant	Exon 9 of 16	ENST00000317799.10	NP_000174.1
HADHB	NM_001281512.2	c.641G>A	p.Arg214Gln	missense_variant	Exon 8 of 15		NP_001268441.1
HADHB	NM_001281513.2	c.620G>A	p.Arg207Gln	missense_variant	Exon 10 of 17		NP_001268442.1
HADHB	XM_011532803.2	c.686G>A	p.Arg229Gln	missense_variant	Exon 9 of 16		XP_011531105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADHB	ENST00000317799.10	c.686G>A	p.Arg229Gln	missense_variant	Exon 9 of 16	1	NM_000183.3	ENSP00000325136.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251326 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461650 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727144

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111808

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial trifunctional protein deficiency 1 Pathogenic:1

Nov 28, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial trifunctional protein deficiency 2 Pathogenic:1

Apr 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 02, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30990523) -

not specified Uncertain:1

Apr 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HADHB c.686G>A (p.Arg229Gln) results in a conservative amino acid change located in the Thiolase, N-terminal (IPR020616) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251326 control chromosomes (gnomAD). c.686G>A has been reported in the literature in individuals affected with features of Mitochondrial Trifunctional Protein Deficiency (Madsen_2019, Guan_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30990523, 34712195). ClinVar contains an entry for this variant (Variation ID: 429516). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.4	.;L;.
PhyloP100		9.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.63	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.96	P;D;.
Vest4		0.77
MVP		0.96
MPC		0.35
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.78
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs375654005; hg19: chr2-26502058;