22-41526276-T-A

Variant names:

• chr22-41526276-T-A
• rs368044961
• NM_001098.3:c.1776T>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001098.3(ACO2):​c.1776T>A​(p.Cys592*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C592C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACO2 NM_001098.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0920
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-41526276-T-A is Pathogenic according to our data. Variant chr22-41526276-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1679318.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	NM_001098.3	MANE Select	c.1776T>A	p.Cys592*	stop_gained	Exon 15 of 18	NP_001089.1	Q99798
	POLR3H	NM_001018050.4	MANE Select	c.*3007A>T		3_prime_UTR	Exon 6 of 6	NP_001018060.1	Q9Y535-1
	POLR3H	NM_001282884.2		c.*3007A>T		3_prime_UTR	Exon 7 of 7	NP_001269813.1	Q9Y535-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	ENST00000216254.9	TSL:1 MANE Select	c.1776T>A	p.Cys592*	stop_gained	Exon 15 of 18	ENSP00000216254.4	Q99798
	POLR3H	ENST00000355209.9	TSL:1 MANE Select	c.*3007A>T		3_prime_UTR	Exon 6 of 6	ENSP00000347345.4	Q9Y535-1
	ACO2	ENST00000878390.1		c.1992T>A	p.Cys664*	stop_gained	Exon 17 of 20	ENSP00000548449.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Infantile cerebellar-retinal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		0.092
Vest4		0.96
GERP RS		-2.5
Mutation Taster		=4/196	disease causing (fs/PTC)

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: rs368044961; hg19: chr22-41922280;