NM_004135.4:c.37G>C

Variant names:

• chrX-153794290-C-G
• rs2092123848
• NM_004135.4:c.37G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004135.4(IDH3G):​c.37G>C​(p.Ala13Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000369 in 1,083,579 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: IDH3G NM_004135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14
• Publications: 0 publications found

Genes affected

IDH3G (HGNC:5386): (isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit gamma) 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 gamma subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. This gene is a candidate gene for periventricular heterotopia. Several alternatively spliced transcript variants of this gene have been described, but only some of their full length natures have been determined. [provided by RefSeq, Jul 2008]

SSR4 (HGNC:11326): (signal sequence receptor subunit 4) This gene encodes the delta subunit of the translocon-associated protein complex which is involved in translocating proteins across the endoplasmic reticulum membrane. The encoded protein is located in the Xq28 region and is arranged in a compact head-to-head manner with the isocitrate dehydrogenase 3 (NAD+) gamma gene and both genes are driven by a CpG-embedded bidirectional promoter. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2011]

SSR4 Gene-Disease associations (from GenCC):

• SSR4-congenital disorder of glycosylation

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2812177).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004135.4. 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
	IDH3G	NM_004135.4	MANE Select	c.37G>C	p.Ala13Pro	missense	Exon 1 of 13	NP_004126.1	P51553-1
	IDH3G	NM_174869.3		c.37G>C	p.Ala13Pro	missense	Exon 1 of 12	NP_777358.1	P51553-2
	SSR4	NM_001440795.1		c.-35C>G		5_prime_UTR	Exon 1 of 7	NP_001427724.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH3G	ENST00000217901.10	TSL:1 MANE Select	c.37G>C	p.Ala13Pro	missense	Exon 1 of 13	ENSP00000217901.5	P51553-1
	IDH3G	ENST00000958656.1		c.37G>C	p.Ala13Pro	missense	Exon 1 of 14	ENSP00000628715.1
	IDH3G	ENST00000958648.1		c.37G>C	p.Ala13Pro	missense	Exon 1 of 13	ENSP00000628707.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000369 AC: 4 AN: 1083579 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 1 AN XY: 354471

African (AFR) AF: 0.00 AC: 0 AN: 26205

American (AMR) AF: 0.00 AC: 0 AN: 34741

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19215

East Asian (EAS) AF: 0.00 AC: 0 AN: 29799

South Asian (SAS) AF: 0.0000753 AC: 4 AN: 53153

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836827

Other (OTH) AF: 0.00 AC: 0 AN: 45475

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.13
Sift	Benign	0.14	T
Sift4G	Benign	0.25	T
Polyphen		0.0010	B
Vest4		0.36
MutPred		0.55		Loss of helix (P = 0.0033)
MVP		0.44
MPC		1.4
ClinPred		0.062	T
GERP RS		4.3
PromoterAI		-0.053	Neutral
Varity_R		0.21
gMVP		0.68
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2092123848; hg19: chrX-153059745;