11-47422842-G-T

Variant names:

• chr11-47422842-G-T
• NM_002804.5:c.723C>A
• PSMC3 p.Ala241Ala

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_002804.5(PSMC3):​c.723C>A​(p.Ala241Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A241A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMC3 NM_002804.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.547
• Publications: 0 publications found

Genes affected

PSMC3 (HGNC:9549): (proteasome 26S subunit, ATPase 3) 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 that have chaperone-like activity. This subunit may compete with PSMC2 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex. A pseudogene has been identified on chromosome 9. [provided by RefSeq, Jul 2008]

PSMC3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• deafness, cataract, impaired intellectual development, and polyneuropathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=-0.547 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002804.5. 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
	PSMC3	NM_002804.5	MANE Select	c.723C>A	p.Ala241Ala	synonymous	Exon 7 of 12	NP_002795.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMC3	ENST00000298852.8	TSL:1 MANE Select	c.723C>A	p.Ala241Ala	synonymous	Exon 7 of 12	ENSP00000298852.3	P17980
	PSMC3	ENST00000619920.4	TSL:1	c.723C>A	p.Ala241Ala	synonymous	Exon 7 of 12	ENSP00000481029.1	P17980
	PSMC3	ENST00000602866.5	TSL:1	c.675C>A	p.Ala225Ala	synonymous	Exon 7 of 12	ENSP00000473652.1	R4GNH3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.37
DANN	Benign	0.83
PhyloP100		-0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-47444393;