15-78168986-G-T

Variant names:

• chr15-78168986-G-T
• rs1595874578
• NM_005530.3:c.1082G>T

Variant summary

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

The NM_005530.3(IDH3A):​c.1082G>T​(p.Arg361Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,446,058 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R361Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IDH3A NM_005530.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.12
• Publications: 0 publications found

Genes affected

IDH3A (HGNC:5384): (isocitrate dehydrogenase (NAD(+)) 3 catalytic subunit alpha) Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the alpha subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. [provided by RefSeq, Jul 2008]

ACSBG1 (HGNC:29567): (acyl-CoA synthetase bubblegum family member 1) The protein encoded by this gene possesses long-chain acyl-CoA synthetase activity. It is thought to play a central role in brain very long-chain fatty acids metabolism and myelinogenesis. [provided by RefSeq, Jul 2008]

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_005530.3. 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
	IDH3A	NM_005530.3	MANE Select	c.1082G>T	p.Arg361Leu	missense	Exon 11 of 11	NP_005521.1	P50213-1
	ACSBG1	NM_015162.5	MANE Select	c.*2458C>A		3_prime_UTR	Exon 14 of 14	NP_055977.3
	ACSBG1	NM_001199377.2		c.*2458C>A		3_prime_UTR	Exon 14 of 14	NP_001186306.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH3A	ENST00000299518.7	TSL:1 MANE Select	c.1082G>T	p.Arg361Leu	missense	Exon 11 of 11	ENSP00000299518.2	P50213-1
	ACSBG1	ENST00000258873.9	TSL:1 MANE Select	c.*2458C>A		3_prime_UTR	Exon 14 of 14	ENSP00000258873.4	Q96GR2
	IDH3A	ENST00000558535.1	TSL:1	n.1030G>T		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1446058 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 717864

⚠️ 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: 33316

American (AMR) AF: 0.00 AC: 0 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.00 AC: 0 AN: 85460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098852

Other (OTH) AF: 0.00 AC: 0 AN: 59686

⚠️ 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	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.41
Sift	Benign	0.041	D
Sift4G	Uncertain	0.047	D
Polyphen		0.69	P
Vest4		0.64
MutPred		0.47		Loss of disorder (P = 0.0268)
MVP		0.72
MPC		1.3
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.51
gMVP		0.89

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: rs1595874578; hg19: chr15-78461328;