dbSNP rs1553505302: HIBCH:p.Leu124Pro (chr2-190290419-A-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_014362.4(HIBCH):c.371T>C(p.Leu124Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HIBCH
NM_014362.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.20

Publications

0 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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 2-190290419-A-G is Pathogenic according to our data. Variant chr2-190290419-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521306.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.371T>C	p.Leu124Pro	missense_variant	Exon 5 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.371T>C	p.Leu124Pro	missense_variant	Exon 5 of 14	1	NM_014362.4	ENSP00000352706.5	Q6NVY1-1
HIBCH	ENST00000392332.7 link	c.371T>C	p.Leu124Pro	missense_variant	Exon 5 of 13	1		ENSP00000376144.3	Q6NVY1-2
HIBCH	ENST00000409934.1 link	c.533T>C	p.Leu178Pro	missense_variant	Exon 5 of 8	3		ENSP00000387247.1	B8ZZZ0
HIBCH	ENST00000392333.7 link	n.65T>C		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000376145.3	H7BYI7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724452

African (AFR)

AF:

0.00

AC:

AN:

33332

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

86124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106168

Other (OTH)

AF:

0.00

AC:

AN:

60152

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Oct 07, 2016

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

.;D;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;T

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Uncertain

2.5

M;M;.

PhyloP100

7.2

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.4

D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;.

Polyphen

1.0

D;D;.

Vest4

0.94

MutPred

0.86

Loss of stability (P = 0.04);Loss of stability (P = 0.04);.;

MVP

0.95

MPC

0.30

ClinPred

1.0

GERP RS

5.4

Varity_R

0.99

gMVP

0.99

Mutation Taster

=22/78

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over