chr2-190205225-A-C

Position:

• chr2-190205225-A-C

Variant summary

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

The NM_014362.4(HIBCH):​c.1053T>G​(p.Ile351Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HIBCH NM_014362.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIBCH	NM_014362.4	c.1053T>G	p.Ile351Met	missense_variant	14/14	ENST00000359678.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIBCH	ENST00000359678.10	c.1053T>G	p.Ile351Met	missense_variant	14/14	1	NM_014362.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 664250). This variant has not been reported in the literature in individuals affected with HIBCH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 351 of the HIBCH protein (p.Ile351Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;D
Eigen	Benign	0.092
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.69	P;.
Vest4		0.43
MutPred		0.76		Gain of disorder (P = 0.0285);.;
MVP		0.78
MPC		0.11
ClinPred		0.98	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.44

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: rs1575690635; hg19: chr2-191069951;