22-41526241-C-CCTCTCTA

Position:

• chr22-41526241-C-CCTCTCTA

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001018050.4(POLR3H):​c.*3041_*3042insTAGAGAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000685 in 1,606,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: POLR3H NM_001018050.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.429

Genes affected

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 22-41526241-C-CCTCTCTA is Benign according to our data. Variant chr22-41526241-C-CCTCTCTA is described in ClinVar as [Likely_benign]. Clinvar id is 1254798.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3H	NM_001018050.4	c.*3041_*3042insTAGAGAG		3_prime_UTR_variant	6/6	ENST00000355209.9	NP_001018060.1
ACO2	NM_001098.3	c.1762-18_1762-12dup		intron_variant		ENST00000216254.9	NP_001089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3H	ENST00000355209.9	c.*3041_*3042insTAGAGAG		3_prime_UTR_variant	6/6	1	NM_001018050.4	ENSP00000347345	P1
ACO2	ENST00000216254.9	c.1762-18_1762-12dup		intron_variant		1	NM_001098.3	ENSP00000216254	P3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000725 AC: 18 AN: 248372 Hom.: 0 AF XY: 0.0000522 AC XY: 7 AN XY: 134134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000803

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000694 AC: 101 AN: 1454576 Hom.: 0 Cov.: 30 AF XY: 0.0000705 AC XY: 51 AN XY: 723044

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000934

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000596

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74368

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000982

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs758197748; hg19: chr22-41922245;