rs864309499

Variant names:

• chr22-41526319-C-T
• rs864309499
• NM_001098.3:c.1819C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001098.3(ACO2):​c.1819C>T​(p.Arg607Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R607H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACO2 NM_001098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.91
• Publications: 9 publications found

Genes affected

ACO2 (HGNC:118): (aconitase 2) The protein encoded by this gene belongs to the aconitase/IPM isomerase family. It is an enzyme that catalyzes the interconversion of citrate to isocitrate via cis-aconitate in the second step of the TCA cycle. This protein is encoded in the nucleus and functions in the mitochondrion. It was found to be one of the mitochondrial matrix proteins that are preferentially degraded by the serine protease 15(PRSS15), also known as Lon protease, after oxidative modification. [provided by RefSeq, Jul 2008]

POLR3H (HGNC:30349): (RNA polymerase III subunit H) Enables DNA-directed 5'-3' RNA polymerase activity. Involved in transcription by RNA polymerase III. Located in centrosome and nucleoplasm. Part of RNA polymerase III complex. [provided by Alliance of Genome Resources, Apr 2022]

POLR3H Gene-Disease associations (from GenCC):

• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity ACON_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 22-41526319-C-T is Pathogenic according to our data. Variant chr22-41526319-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218316.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098.3. 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
	ACO2	NM_001098.3	MANE Select	c.1819C>T	p.Arg607Cys	missense	Exon 15 of 18	NP_001089.1
	POLR3H	NM_001018050.4	MANE Select	c.*2964G>A		3_prime_UTR	Exon 6 of 6	NP_001018060.1
	POLR3H	NM_001282884.2		c.*2964G>A		3_prime_UTR	Exon 7 of 7	NP_001269813.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	ENST00000216254.9	TSL:1 MANE Select	c.1819C>T	p.Arg607Cys	missense	Exon 15 of 18	ENSP00000216254.4
	POLR3H	ENST00000355209.9	TSL:1 MANE Select	c.*2964G>A		3_prime_UTR	Exon 6 of 6	ENSP00000347345.4
	ACO2	ENST00000878390.1		c.2035C>T	p.Arg679Cys	missense	Exon 17 of 20	ENSP00000548449.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250904 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460558 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726590

African (AFR) AF: 0.0000299 AC: 1 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4688

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60270

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Infantile cerebellar-retinal degeneration (2)
-	1	-	not provided (1)
1	-	-	Optic atrophy 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		3.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.87		Loss of sheet (P = 0.0457)
MVP		0.87
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.96
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs864309499; hg19: chr22-41922323; COSMIC: COSV53442569; COSMIC: COSV53442569;