14-90263394-A-G

Position:

• chr14-90263394-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002802.3(PSMC1):​c.231A>G​(p.Glu77=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,593,456 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (21 hom.)
• Consequence: PSMC1 NM_002802.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.300

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 14-90263394-A-G is Benign according to our data. Variant chr14-90263394-A-G is described in ClinVar as [Benign]. Clinvar id is 770241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.3 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMC1	NM_002802.3	c.231A>G	p.Glu77=	synonymous_variant	4/11	ENST00000261303.13	NP_002793.2
PSMC1	NM_001330212.2	c.12A>G	p.Glu4=	synonymous_variant	5/12		NP_001317141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMC1	ENST00000261303.13	c.231A>G	p.Glu77=	synonymous_variant	4/11	1	NM_002802.3	ENSP00000261303	P1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152246 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00981

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00346 AC: 813 AN: 235156 Hom.: 5 AF XY: 0.00341 AC XY: 435 AN XY: 127458

Gnomad AFR exome AF: 0.000847

Gnomad AMR exome AF: 0.00871

Gnomad ASJ exome AF: 0.000841

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00424

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00332 AC: 4781 AN: 1441092 Hom.: 21 Cov.: 31 AF XY: 0.00333 AC XY: 2385 AN XY: 716742

Gnomad4 AFR exome AF: 0.000682

Gnomad4 AMR exome AF: 0.00864

Gnomad4 ASJ exome AF: 0.000701

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00385

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.00347

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00299 AC: 456 AN: 152364 Hom.: 1 Cov.: 33 AF XY: 0.00322 AC XY: 240 AN XY: 74506

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00986

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00293 Hom.: 0

Bravo AF: 0.00398

EpiCase AF: 0.00333

EpiControl AF: 0.00338

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.3
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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: rs143172121; hg19: chr14-90729738;