rs371063501

Variant names:

• chr7-27649496-C-A
• rs371063501
• NM_152740.4:c.229G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-27649496-C-A
• chr7-27649496-C-G
• chr7-27649496-C-T

Variant summary

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

The NM_152740.4(HIBADH):​c.229G>T​(p.Glu77*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HIBADH NM_152740.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.229G>T	p.Glu77*	stop_gained	Exon 2 of 8	NP_689953.1	P31937
	HIBADH	NM_001430749.1		c.-52+13202G>T		intron	N/A	NP_001417678.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIBADH	ENST00000265395.7	TSL:1 MANE Select	c.229G>T	p.Glu77*	stop_gained	Exon 2 of 8	ENSP00000265395.2	P31937
	HIBADH	ENST00000879285.1		c.229G>T	p.Glu77*	stop_gained	Exon 2 of 10	ENSP00000549344.1
	HIBADH	ENST00000939048.1		c.229G>T	p.Glu77*	stop_gained	Exon 2 of 9	ENSP00000609107.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460514 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726454

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 85902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111480

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.6
Vest4		0.41
GERP RS		6.0
Mutation Taster		=6/194	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371063501; hg19: chr7-27689115;