Genetic Variant NM_152740.4:c.620C>A (chr7-27538416-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_152740.4(HIBADH):c.620C>A(p.Ala207Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HIBADH
NM_152740.4 missense, splice_region

Scores

Splicing: ADA: 0.9988

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86

Publications

2 publications found

Variant links:

Genes affected

HIBADH (HGNC:4907): (3-hydroxyisobutyrate dehydrogenase) This gene encodes a mitochondrial 3-hydroxyisobutyrate dehydrogenase enzyme. The encoded protein plays a critical role in the catabolism of L-valine by catalyzing the oxidation of 3-hydroxyisobutyrate to methylmalonate semialdehyde. [provided by RefSeq, Nov 2011]

HIBADH Gene-Disease associations (from GenCC):

3-hydroxyisobutyric aciduria
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
inborn organic aciduria
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

HIBADH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152740.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIBADH	NM_152740.4	MANE Select	c.620C>A	p.Ala207Glu	missense splice_region	Exon 6 of 8	NP_689953.1	P31937
	HIBADH	NM_001430749.1		c.317C>A	p.Ala106Glu	missense splice_region	Exon 5 of 7	NP_001417678.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HIBADH	ENST00000265395.7	TSL:1 MANE Select	c.620C>A	p.Ala207Glu	missense splice_region	Exon 6 of 8	ENSP00000265395.2	P31937
HIBADH	ENST00000879285.1		c.812C>A	p.Ala271Glu	missense splice_region	Exon 8 of 10	ENSP00000549344.1
HIBADH	ENST00000939048.1		c.746C>A	p.Ala249Glu	missense splice_region	Exon 7 of 9	ENSP00000609107.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.00

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110380

Other (OTH)

AF:

0.00

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.067

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.32

MutationAssessor

Pathogenic

4.1

PhyloP100

7.9

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.92

MutPred

0.61

Gain of helix (P = 0.0325)

MVP

0.74

MPC

0.34

ClinPred

1.0

GERP RS

6.0

Varity_R

0.92

gMVP

0.98

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over