7-27538378-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_152740.4(HIBADH):ā€‹c.658A>Gā€‹(p.Met220Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

HIBADH
NM_152740.4 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.87
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HIBADHNM_152740.4 linkuse as main transcriptc.658A>G p.Met220Val missense_variant 6/8 ENST00000265395.7
HIBADHXM_047419834.1 linkuse as main transcriptc.355A>G p.Met119Val missense_variant 5/7
HIBADHXM_047419835.1 linkuse as main transcriptc.355A>G p.Met119Val missense_variant 5/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HIBADHENST00000265395.7 linkuse as main transcriptc.658A>G p.Met220Val missense_variant 6/81 NM_152740.4 P1
HIBADHENST00000425715.1 linkuse as main transcriptc.487A>G p.Met163Val missense_variant 5/62
HIBADHENST00000428288.2 linkuse as main transcriptc.*377A>G 3_prime_UTR_variant, NMD_transcript_variant 5/73

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
249590
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
135028
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000218
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1460896
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
726728
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 05, 2023The c.658A>G (p.M220V) alteration is located in exon 6 (coding exon 6) of the HIBADH gene. This alteration results from a A to G substitution at nucleotide position 658, causing the methionine (M) at amino acid position 220 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Uncertain
0.050
T
BayesDel_noAF
Uncertain
0.13
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
T
Eigen
Uncertain
0.65
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Benign
0.058
D
MetaRNN
Pathogenic
0.82
D
MetaSVM
Benign
-0.85
T
MutationAssessor
Uncertain
2.8
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-3.8
D
REVEL
Uncertain
0.49
Sift
Benign
0.031
D
Sift4G
Uncertain
0.034
D
Polyphen
0.84
P
Vest4
0.95
MutPred
0.62
Gain of catalytic residue at M220 (P = 0.1758);
MVP
0.34
MPC
0.29
ClinPred
0.73
D
GERP RS
6.2
Varity_R
0.77
gMVP
0.94

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs765161843; hg19: chr7-27577997; API