rs757976755

chr2-190296836-G-Achr2-190296836-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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 Uncertain significance (★). 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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 2.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIBCH	NM_014362.4	c.196C>T	p.Arg66Trp	missense_variant	3/14	ENST00000359678.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIBCH	ENST00000359678.10	c.196C>T	p.Arg66Trp	missense_variant	3/14	1	NM_014362.4	P1
HIBCH	ENST00000392332.7	c.196C>T	p.Arg66Trp	missense_variant	3/13	1
HIBCH	ENST00000409934.1	c.358C>T	p.Arg120Trp	missense_variant	3/8	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251378 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135876

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461612 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beta-hydroxyisobutyryl-CoA deacylase deficiency Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2015	- -
Pathogenic, no assertion criteria provided	research	Bonnen Lab, Baylor College of Medicine	Dec 30, 2014	Decreased HIBCH enzymatic activity in fibroblasts. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2018	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported as homozygous in an individual affected with 3-Hydroxyisobutryl-CoA hydrolase deficiency (PMID: 26026795). ClinVar contains an entry for this variant (Variation ID: 190268). This variant is present in population databases (rs757976755, ExAC 0.003%). This sequence change replaces arginine with tryptophan at codon 66 of the HIBCH protein (p.Arg66Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.22	T
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	D
GERP RS		3.5
Varity_R		0.76
gMVP		0.66

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: rs757976755; hg19: chr2-191161562; COSMIC: COSV100676117;