7-27632370-T-C

Position:

• chr7-27632370-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152740.4(HIBADH):​c.328A>G​(p.Ile110Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: HIBADH NM_152740.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.159

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050439864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIBADH	NM_152740.4	c.328A>G	p.Ile110Val	missense_variant	3/8	ENST00000265395.7	NP_689953.1
HIBADH	XM_047419834.1	c.25A>G	p.Ile9Val	missense_variant	2/7		XP_047275790.1
HIBADH	XM_047419835.1	c.25A>G	p.Ile9Val	missense_variant	2/7		XP_047275791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIBADH	ENST00000265395.7	c.328A>G	p.Ile110Val	missense_variant	3/8	1	NM_152740.4	ENSP00000265395.2
HIBADH	ENST00000425715.1	c.154A>G	p.Ile52Val	missense_variant	2/6	2		ENSP00000390205.1
HIBADH	ENST00000428288.2	n.*47A>G		non_coding_transcript_exon_variant	2/7	3		ENSP00000393365.1
HIBADH	ENST00000428288.2	n.*47A>G		3_prime_UTR_variant	2/7	3		ENSP00000393365.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460666 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.2
DANN	Benign	0.50
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.47	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.016
Sift	Benign	0.67	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.39		Gain of helix (P = 0.132);
MVP		0.095
MPC		0.041
ClinPred		0.036	T
GERP RS		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.020
gMVP		0.27

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

Other links and lift over

dbSNP: rs1785762483; hg19: chr7-27671989;