14-90263727-C-T

Position:

• chr14-90263727-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002802.3(PSMC1):​c.345C>T​(p.Ile115=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 152,056 control chromosomes in the GnomAD database, including 23,785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23785 hom., cov: 32)
  • Exomes 𝑓: 0.59 (258474 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSMC1 NM_002802.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.53

Genes affected

PSMC1 (HGNC:9547): (proteasome 26S subunit, ATPase 1) 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. This subunit and a 20S core alpha subunit interact specifically with the hepatitis B virus X protein, a protein critical to viral replication. This subunit also interacts with the adenovirus E1A protein and this interaction alters the activity of the proteasome. Finally, this subunit interacts with ataxin-7, suggesting a role for the proteasome in the development of spinocerebellar ataxia type 7, a progressive neurodegenerative disorder. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 14-90263727-C-T is Benign according to our data. Variant chr14-90263727-C-T is described in ClinVar as [Benign]. Clinvar id is 1302301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMC1	NM_002802.3	c.345C>T	p.Ile115=	synonymous_variant	5/11	ENST00000261303.13	NP_002793.2
PSMC1	NM_001330212.2	c.126C>T	p.Ile42=	synonymous_variant	6/12		NP_001317141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMC1	ENST00000261303.13	c.345C>T	p.Ile115=	synonymous_variant	5/11	1	NM_002802.3	ENSP00000261303	P1

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83767 AN: 151938 Hom.: 23773 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.614

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.581

GnomAD3 exomes AF: 0.596 AC: 149327 AN: 250710 Hom.: 45164 AF XY: 0.600 AC XY: 81449 AN XY: 135736

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.652

Gnomad ASJ exome AF: 0.674

Gnomad EAS exome AF: 0.482

Gnomad SAS exome AF: 0.626

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.604

Gnomad OTH exome AF: 0.624

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.593 AC: 865202 AN: 1459156 Hom.: 258474 Cov.: 35 AF XY: 0.595 AC XY: 432306 AN XY: 726044

Gnomad4 AFR exome AF: 0.408

Gnomad4 AMR exome AF: 0.648

Gnomad4 ASJ exome AF: 0.676

Gnomad4 EAS exome AF: 0.488

Gnomad4 SAS exome AF: 0.628

Gnomad4 FIN exome AF: 0.599

Gnomad4 NFE exome AF: 0.595

Gnomad4 OTH exome AF: 0.593

GnomAD4 genome AF: 0.551 AC: 83823 AN: 152056 Hom.: 23785 Cov.: 32 AF XY: 0.553 AC XY: 41065 AN XY: 74322

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.625

Gnomad4 ASJ AF: 0.683

Gnomad4 EAS AF: 0.483

Gnomad4 SAS AF: 0.613

Gnomad4 FIN AF: 0.592

Gnomad4 NFE AF: 0.603

Gnomad4 OTH AF: 0.585

Alfa AF: 0.602 Hom.: 10191

Bravo AF: 0.545

Asia WGS AF: 0.561 AC: 1953 AN: 3478

EpiCase AF: 0.612

EpiControl AF: 0.612

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs4811; hg19: chr14-90730071; COSMIC: COSV54320313; COSMIC: COSV54320313;