rs757976755

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_014362.4(HIBCH):c.196C>T(p.Arg66Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,612 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. R66Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

HIBCH
NM_014362.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 2.46

Publications

6 publications found

Variant links:

Genes affected

HIBCH (HGNC:4908): (3-hydroxyisobutyryl-CoA hydrolase) This gene encodes the enzyme responsible for hydrolysis of both HIBYL-CoA and beta-hydroxypropionyl-CoA. Mutations in this gene have been associated with 3-hyroxyisobutyryl-CoA hydrolase deficiency. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

HIBCH Gene-Disease associations (from GenCC):

3-hydroxyisobutyryl-CoA hydrolase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

HIBCH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

PP5

Variant 2-190296836-G-A is Pathogenic according to our data. Variant chr2-190296836-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 190268.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIBCH	NM_014362.4 link	c.196C>T	p.Arg66Trp	missense_variant	Exon 3 of 14	ENST00000359678.10	NP_055177.2	Q6NVY1-1A0A140VJL0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HIBCH	ENST00000359678.10 link	c.196C>T	p.Arg66Trp	missense_variant	Exon 3 of 14	1	NM_014362.4	ENSP00000352706.5	Q6NVY1-1
HIBCH	ENST00000392332.7 link	c.196C>T	p.Arg66Trp	missense_variant	Exon 3 of 13	1		ENSP00000376144.3	Q6NVY1-2
HIBCH	ENST00000409934.1 link	c.358C>T	p.Arg120Trp	missense_variant	Exon 3 of 8	3		ENSP00000387247.1	B8ZZZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251378

AF XY:

0.0000147

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111776

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000994

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

3-hydroxyisobutyryl-CoA hydrolase deficiency

Pathogenic:3

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 66 of the HIBCH protein (p.Arg66Trp). This variant is present in population databases (rs757976755, gnomAD 0.003%). This missense change has been observed in individual(s) with 3-Hydroxyisobutryl-CoA hydrolase deficiency (PMID: 26026795; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190268). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HIBCH protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Dec 30, 2014

Bonnen Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Decreased HIBCH enzymatic activity in fibroblasts. -

Aug 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

.;D;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.3

M;M;.

PhyloP100

2.5

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-6.4

D;D;D

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0020

D;D;.

Polyphen

1.0

D;D;.

Vest4

0.65

MutPred

0.55

Loss of MoRF binding (P = 0.1029);Loss of MoRF binding (P = 0.1029);.;

MVP

0.94

MPC

0.20

ClinPred

0.98

GERP RS

3.5

Varity_R

0.76

gMVP

0.66

Mutation Taster

=5/95

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over