rs6945993

Variant names:

• chr7-27641391-A-G
• rs6945993
• NM_152740.4:c.252+8082T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152740.4(HIBADH):​c.252+8082T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 151,980 control chromosomes in the GnomAD database, including 44,103 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (44103 hom., cov: 30)
• Consequence: HIBADH NM_152740.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIBADH	NM_152740.4	c.252+8082T>C		intron_variant	Intron 2 of 7	ENST00000265395.7	NP_689953.1
HIBADH	NM_001430749.1	c.-51-8946T>C		intron_variant	Intron 1 of 6		NP_001417678.1
HIBADH	XM_047419834.1	c.-52+7157T>C		intron_variant	Intron 1 of 6		XP_047275790.1
HIBADH	XM_047419835.1	c.-52+5761T>C		intron_variant	Intron 1 of 6		XP_047275791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIBADH	ENST00000265395.7	c.252+8082T>C		intron_variant	Intron 2 of 7	1	NM_152740.4	ENSP00000265395.2
HIBADH	ENST00000425715.1	c.82+6282T>C		intron_variant	Intron 1 of 5	2		ENSP00000390205.1
HIBADH	ENST00000428288.2	n.92-8946T>C		intron_variant	Intron 1 of 6	3		ENSP00000393365.1

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115121 AN: 151862 Hom.: 44059 Cov.: 30

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.704

Gnomad MID AF: 0.777

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.761

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.758 AC: 115220 AN: 151980 Hom.: 44103 Cov.: 30 AF XY: 0.757 AC XY: 56208 AN XY: 74286

African (AFR) AF: 0.863 AC: 35772 AN: 41474

American (AMR) AF: 0.735 AC: 11227 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 2785 AN: 3472

East Asian (EAS) AF: 0.944 AC: 4867 AN: 5156

South Asian (SAS) AF: 0.708 AC: 3406 AN: 4812

European-Finnish (FIN) AF: 0.704 AC: 7436 AN: 10558

Middle Eastern (MID) AF: 0.774 AC: 226 AN: 292

European-Non Finnish (NFE) AF: 0.697 AC: 47319 AN: 67920

Other (OTH) AF: 0.762 AC: 1610 AN: 2114

Alfa AF: 0.711 Hom.: 16858

Bravo AF: 0.771

Asia WGS AF: 0.839 AC: 2918 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.64
PhyloP100		0.065
Mutation Taster		=100/0	polymorphism (auto)

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: rs6945993; hg19: chr7-27681010;