2-190205194-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014362.4(HIBCH):c.1084G>A(p.Ala362Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,456,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: HIBCH NM_014362.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21477267).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIBCH	NM_014362.4	c.1084G>A	p.Ala362Thr	missense_variant	14/14	ENST00000359678.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIBCH	ENST00000359678.10	c.1084G>A	p.Ala362Thr	missense_variant	14/14	1	NM_014362.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248252 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000902

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456784 Hom.: 0 Cov.: 28 AF XY: 0.00000552 AC XY: 4 AN XY: 725190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beta-hydroxyisobutyryl-CoA deacylase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 01, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 362 of the HIBCH protein (p.Ala362Thr). This variant is present in population databases (rs375193143, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with HIBCH-related conditions. 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T;D
Eigen	Benign	-0.016
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.083
Sift	Benign	0.13	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.11	B;.
Vest4		0.28
MutPred		0.32		Gain of phosphorylation at A362 (P = 0.0607);.;
MVP		0.84
MPC		0.035
ClinPred		0.51	D
GERP RS		4.5
Varity_R		0.20
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs375193143; hg19: chr2-191069920;