17-63829486-T-C

Variant names:

• chr17-63829486-T-C
• rs2665833
• NM_002805.6:c.97-8T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002805.6(PSMC5):​c.97-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 1,551,736 control chromosomes in the GnomAD database, including 315,042 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38032 hom., cov: 32)
  • Exomes 𝑓: 0.63 (277010 hom.)
• Consequence: PSMC5 NM_002805.6 splice_region, intron
• Scores: Splicing: ADA: 0.00008497
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.831

Genes affected

PSMC5 (HGNC:9552): (proteasome 26S subunit, ATPase 5) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. In addition to participation in proteasome functions, this subunit may participate in transcriptional regulation since it has been shown to interact with the thyroid hormone receptor and retinoid X receptor-alpha. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

FTSJ3 (HGNC:17136): (FtsJ RNA 2'-O-methyltransferase 3) Although the function of this gene is not known, the existence of this gene is supported by mRNA and EST data. A possible function of the encoded protein can be inferred from amino acid sequence similarity to the E.coli FtsJ protein and to a mouse protein possibly involved in embryogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-63829486-T-C is Benign according to our data. Variant chr17-63829486-T-C is described in ClinVar as [Benign]. Clinvar id is 1302788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMC5	NM_002805.6	c.97-8T>C		splice_region_variant, intron_variant	Intron 2 of 11	ENST00000310144.11	NP_002796.4
PSMC5	NM_001199163.2	c.73-8T>C		splice_region_variant, intron_variant	Intron 2 of 11		NP_001186092.1
PSMC5	XM_047436423.1	c.97-8T>C		splice_region_variant, intron_variant	Intron 2 of 7		XP_047292379.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMC5	ENST00000310144.11	c.97-8T>C		splice_region_variant, intron_variant	Intron 2 of 11	1	NM_002805.6	ENSP00000310572.6

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105606 AN: 151964 Hom.: 37973 Cov.: 32

Gnomad AFR AF: 0.900

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.655

GnomAD3 exomes AF: 0.643 AC: 102261 AN: 158940 Hom.: 33575 AF XY: 0.645 AC XY: 53941 AN XY: 83688

Gnomad AFR exome AF: 0.911

Gnomad AMR exome AF: 0.626

Gnomad ASJ exome AF: 0.519

Gnomad EAS exome AF: 0.566

Gnomad SAS exome AF: 0.738

Gnomad FIN exome AF: 0.651

Gnomad NFE exome AF: 0.608

Gnomad OTH exome AF: 0.618

GnomAD4 exome AF: 0.626 AC: 876250 AN: 1399654 Hom.: 277010 Cov.: 40 AF XY: 0.628 AC XY: 433370 AN XY: 690560

Gnomad4 AFR exome AF: 0.913

Gnomad4 AMR exome AF: 0.631

Gnomad4 ASJ exome AF: 0.525

Gnomad4 EAS exome AF: 0.593

Gnomad4 SAS exome AF: 0.736

Gnomad4 FIN exome AF: 0.650

Gnomad4 NFE exome AF: 0.612

Gnomad4 OTH exome AF: 0.625

GnomAD4 genome AF: 0.695 AC: 105721 AN: 152082 Hom.: 38032 Cov.: 32 AF XY: 0.695 AC XY: 51679 AN XY: 74326

Gnomad4 AFR AF: 0.900

Gnomad4 AMR AF: 0.632

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.576

Gnomad4 SAS AF: 0.748

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.610

Gnomad4 OTH AF: 0.653

Alfa AF: 0.622 Hom.: 48620

Bravo AF: 0.699

Asia WGS AF: 0.685 AC: 2382 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.2
DANN	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000085
dbscSNV1_RF	Benign	0.010
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

Publications

LitVar

Other links and lift over

dbSNP: rs2665833; hg19: chr17-61906846;