15-78168948-T-G

Variant names:

• chr15-78168948-T-G
• rs1017642843
• NM_005530.3:c.1044T>G

Variant summary

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

The NM_005530.3(IDH3A):​c.1044T>G​(p.Asn348Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N348N) has been classified as Likely benign.

• 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: -0.309
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11253598).

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.1044T>G	p.Asn348Lys	missense	Exon 11 of 11	NP_005521.1	P50213-1
	ACSBG1	NM_015162.5	MANE Select	c.*2496A>C		3_prime_UTR	Exon 14 of 14	NP_055977.3
	ACSBG1	NM_001199377.2		c.*2496A>C		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.1044T>G	p.Asn348Lys	missense	Exon 11 of 11	ENSP00000299518.2	P50213-1
	ACSBG1	ENST00000258873.9	TSL:1 MANE Select	c.*2496A>C		3_prime_UTR	Exon 14 of 14	ENSP00000258873.4	Q96GR2
	IDH3A	ENST00000558535.1	TSL:1	n.992T>G		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451528 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 720940

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.00 AC: 0 AN: 85622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103644

Other (OTH) AF: 0.0000167 AC: 1 AN: 59912

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.88
DANN	Benign	0.85
DEOGEN2	Benign	0.41	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.28	N
PhyloP100		-0.31
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.99	T
Polyphen		0.0	B
Vest4		0.39
MutPred		0.43		Gain of ubiquitination at N348 (P = 0.0203)
MVP		0.34
MPC		0.99
ClinPred		0.11	T
GERP RS		-4.1
Varity_R		0.25
gMVP		0.85

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: rs1017642843; hg19: chr15-78461290;