7-27662719-C-A

Variant names:

• chr7-27662719-C-A
• rs934091125
• NM_152740.4:c.70G>T

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.70G>T​(p.Ala24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000816 in 1,225,828 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. A24T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: HIBADH NM_152740.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• 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=0.11439872).

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.70G>T	p.Ala24Ser	missense	Exon 1 of 8	NP_689953.1	P31937
	HIBADH	NM_001430749.1		c.-73G>T		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.70G>T	p.Ala24Ser	missense	Exon 1 of 8	ENSP00000265395.2	P31937
	HIBADH	ENST00000879285.1		c.70G>T	p.Ala24Ser	missense	Exon 1 of 10	ENSP00000549344.1
	HIBADH	ENST00000939048.1		c.70G>T	p.Ala24Ser	missense	Exon 1 of 9	ENSP00000609107.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.16e-7 AC: 1 AN: 1225828 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 595424

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24228

American (AMR) AF: 0.00 AC: 0 AN: 12094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17770

East Asian (EAS) AF: 0.00 AC: 0 AN: 27122

South Asian (SAS) AF: 0.00 AC: 0 AN: 56458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3416

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 991974

Other (OTH) AF: 0.00 AC: 0 AN: 49382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.037
Sift	Benign	0.42	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.46		Gain of disorder (P = 0.0244)
MVP		0.22
MPC		0.045
ClinPred		0.18	T
GERP RS		3.4
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.043
gMVP		0.33
Mutation Taster		=97/3	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: rs934091125; hg19: chr7-27702338;