chr7-27662716-C-T

Variant names:

• chr7-27662716-C-T
• rs901133047
• NM_152740.4:c.73G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152740.4(HIBADH):​c.73G>A​(p.Ala25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A25S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HIBADH NM_152740.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0170
• Publications: 0 publications found

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

LOC105375211 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08714858).

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.73G>A	p.Ala25Thr	missense	Exon 1 of 8	NP_689953.1	P31937
	HIBADH	NM_001430749.1		c.-70G>A		5_prime_UTR	Exon 1 of 7	NP_001417678.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIBADH	ENST00000265395.7	TSL:1 MANE Select	c.73G>A	p.Ala25Thr	missense	Exon 1 of 8	ENSP00000265395.2	P31937
	HIBADH	ENST00000879285.1		c.73G>A	p.Ala25Thr	missense	Exon 1 of 10	ENSP00000549344.1
	HIBADH	ENST00000939048.1		c.73G>A	p.Ala25Thr	missense	Exon 1 of 9	ENSP00000609107.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1222484 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 593430

African (AFR) AF: 0.00 AC: 0 AN: 24190

American (AMR) AF: 0.00 AC: 0 AN: 11806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17594

East Asian (EAS) AF: 0.00 AC: 0 AN: 27100

South Asian (SAS) AF: 0.00 AC: 0 AN: 55740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3424

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 990114

Other (OTH) AF: 0.00 AC: 0 AN: 49222

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.017
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.046
Sift	Benign	0.42	T
Sift4G	Benign	0.69	T
Polyphen		0.023	B
Vest4		0.038
MutPred		0.41		Gain of helix (P = 0.0199)
MVP		0.23
MPC		0.046
ClinPred		0.19	T
GERP RS		3.4
PromoterAI		0.043	Neutral
Varity_R		0.039
gMVP		0.48
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs901133047; hg19: chr7-27702335;