2-190246167-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014362.4(HIBCH):c.796G>A(p.Asp266Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,581,178 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D266D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (17 hom.)
• Consequence: HIBCH NM_014362.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.52

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0078730285).
• BP6: Variant 2-190246167-C-T is Benign according to our data. Variant chr2-190246167-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235593.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00298 (453/152236) while in subpopulation NFE AF= 0.00554 (377/68000). AF 95% confidence interval is 0.00508. There are 2 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIBCH	NM_014362.4	c.796G>A	p.Asp266Asn	missense_variant	10/14	ENST00000359678.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIBCH	ENST00000359678.10	c.796G>A	p.Asp266Asn	missense_variant	10/14	1	NM_014362.4	P1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152118 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00554

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00253 AC: 632 AN: 249884 Hom.: 2 AF XY: 0.00249 AC XY: 336 AN XY: 135178

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000688

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00487

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00438 AC: 6261 AN: 1428942 Hom.: 17 Cov.: 26 AF XY: 0.00424 AC XY: 3025 AN XY: 713134

Gnomad4 AFR exome AF: 0.000761

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000702

Gnomad4 FIN exome AF: 0.000488

Gnomad4 NFE exome AF: 0.00544

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.00298 AC: 453 AN: 152236 Hom.: 2 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74416

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00554

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00415 Hom.: 2

Bravo AF: 0.00288

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00524 AC: 45

ExAC AF: 0.00250 AC: 303

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00507

EpiControl AF: 0.00469

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 12, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	HIBCH: BP4, BS2 -

Beta-hydroxyisobutyryl-CoA deacylase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	0.034
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0079	T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L;L;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.096
Sift	Benign	0.18	T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;.
Polyphen		0.0	B;B;.;.;.
Vest4		0.38
MVP		0.67
MPC		0.034
ClinPred		0.020	T
GERP RS		4.0
Varity_R		0.28
gMVP		0.27

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: rs144053672; hg19: chr2-191110893;