chr22-41528594-TGAAG-T

Variant names:

• chr22-41528594-TGAAG-T
• rs786204830
• NM_001098.3:c.2328_2331delGGAA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001098.3(ACO2):​c.2328_2331delGGAA​(p.Lys776AsnfsTer49) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K776K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACO2 NM_001098.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.05
• Publications: 7 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 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0064 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-41528594-TGAAG-T is Pathogenic according to our data. Variant chr22-41528594-TGAAG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 189314.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	NM_001098.3	MANE Select	c.2328_2331delGGAA	p.Lys776AsnfsTer49	frameshift	Exon 18 of 18	NP_001089.1
	POLR3H	NM_001018050.4	MANE Select	c.*685_*688delCTTC		3_prime_UTR	Exon 6 of 6	NP_001018060.1
	POLR3H	NM_001282884.2		c.*685_*688delCTTC		3_prime_UTR	Exon 7 of 7	NP_001269813.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	ENST00000216254.9	TSL:1 MANE Select	c.2328_2331delGGAA	p.Lys776AsnfsTer49	frameshift	Exon 18 of 18	ENSP00000216254.4
	POLR3H	ENST00000355209.9	TSL:1 MANE Select	c.*685_*688delCTTC		3_prime_UTR	Exon 6 of 6	ENSP00000347345.4
	ACO2	ENST00000396512.3	TSL:5	c.2403_2406delGGAA	p.Lys801AsnfsTer49	frameshift	Exon 18 of 18	ENSP00000379769.3

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Optic atrophy Pathogenic:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Infantile cerebellar-retinal degeneration Pathogenic:1

Dec 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=2/198	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: rs786204830; hg19: chr22-41924598;