7-27649600-A-T

Position:

• chr7-27649600-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152740.4(HIBADH):​c.125T>A​(p.Val42Asp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HIBADH NM_152740.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIBADH	NM_152740.4	c.125T>A	p.Val42Asp	missense_variant	2/8	ENST00000265395.7	NP_689953.1
LOC105375211	XR_007060268.1	n.85+1670A>T		intron_variant
LOC105375211	XR_927139.3	n.85+1670A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIBADH	ENST00000265395.7	c.125T>A	p.Val42Asp	missense_variant	2/8	1	NM_152740.4	ENSP00000265395.2
HIBADH	ENST00000496814.1	n.194T>A		non_coding_transcript_exon_variant	2/2	3
HIBADH	ENST00000428288.2	n.91+13098T>A		intron_variant		3		ENSP00000393365.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2024

The c.125T>A (p.V42D) alteration is located in exon 2 (coding exon 2) of the HIBADH gene. This alteration results from a T to A substitution at nucleotide position 125, causing the valine (V) at amino acid position 42 to be replaced by an aspartic acid (D). 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	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.90		Gain of disorder (P = 0.0172);
MVP		0.76
MPC		0.39
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-27689219;