7-27543001-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_152740.4(HIBADH):ā€‹c.584A>Gā€‹(p.Asn195Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000089 ( 0 hom. )

Consequence

HIBADH
NM_152740.4 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.26
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.30546448).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HIBADHNM_152740.4 linkuse as main transcriptc.584A>G p.Asn195Ser missense_variant 5/8 ENST00000265395.7
HIBADHXM_047419834.1 linkuse as main transcriptc.281A>G p.Asn94Ser missense_variant 4/7
HIBADHXM_047419835.1 linkuse as main transcriptc.281A>G p.Asn94Ser missense_variant 4/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HIBADHENST00000265395.7 linkuse as main transcriptc.584A>G p.Asn195Ser missense_variant 5/81 NM_152740.4 P1
HIBADHENST00000425715.1 linkuse as main transcriptc.413A>G p.Asn138Ser missense_variant 4/62
HIBADHENST00000428288.2 linkuse as main transcriptc.*303A>G 3_prime_UTR_variant, NMD_transcript_variant 4/73

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152078
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
250848
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135538
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461560
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727082
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000269
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
152078
Hom.:
0
Cov.:
31
AF XY:
0.0000673
AC XY:
5
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000718
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 GeneticsJun 27, 2022The c.584A>G (p.N195S) alteration is located in exon 5 (coding exon 5) of the HIBADH gene. This alteration results from a A to G substitution at nucleotide position 584, causing the asparagine (N) at amino acid position 195 to be replaced by a serine (S). 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
Benign
0.091
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.50
D
Eigen
Benign
0.024
Eigen_PC
Benign
0.079
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.31
T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-4.0
D
REVEL
Benign
0.11
Sift
Uncertain
0.017
D
Sift4G
Uncertain
0.050
T
Polyphen
0.021
B
Vest4
0.52
MVP
0.40
MPC
0.080
ClinPred
0.24
T
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.60
gMVP
0.81

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: rs200680648; hg19: chr7-27582620; API