NM_002788.4:c.562C>T

Variant names:

• chr14-58267492-C-T
• rs765244048
• NM_002788.4:c.562C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002788.4(PSMA3):​c.562C>T​(p.Arg188Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,415,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R188H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PSMA3 NM_002788.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• Publications: 1 publications found

Genes affected

PSMA3 (HGNC:9532): (proteasome 20S subunit alpha 3) The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure 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. 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 a member of the peptidase T1A family, that is a 20S core alpha subunit. Two alternative transcripts encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

PSMA3-AS1 (HGNC:26445): (PSMA3 antisense RNA 1)

ARMH4 (HGNC:19846): (armadillo like helical domain containing 4) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000258682 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3669304).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002788.4. 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
	PSMA3	NM_002788.4	MANE Select	c.562C>T	p.Arg188Cys	missense	Exon 8 of 11	NP_002779.1	A0A140VK43
	PSMA3	NM_152132.3		c.541C>T	p.Arg181Cys	missense	Exon 8 of 11	NP_687033.1	P25788-2
	PSMA3	NR_038123.2		n.557C>T		non_coding_transcript_exon	Exon 7 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMA3	ENST00000216455.9	TSL:1 MANE Select	c.562C>T	p.Arg188Cys	missense	Exon 8 of 11	ENSP00000216455.4	P25788-1
	PSMA3	ENST00000412908.6	TSL:1	c.541C>T	p.Arg181Cys	missense	Exon 8 of 11	ENSP00000390491.2	P25788-2
	PSMA3-AS1	ENST00000554360.5	TSL:1	n.447-99G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000457 AC: 1 AN: 218738 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000955

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1415886 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 702986

African (AFR) AF: 0.0000319 AC: 1 AN: 31304

American (AMR) AF: 0.00 AC: 0 AN: 35722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24920

East Asian (EAS) AF: 0.00 AC: 0 AN: 37596

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094194

Other (OTH) AF: 0.00 AC: 0 AN: 58480

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	0.0020	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.074
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.19
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.040	B
Vest4		0.48
MutPred		0.52		Loss of MoRF binding (P = 0.0367)
MVP		0.62
MPC		1.4
ClinPred		0.96	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.67
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs765244048; hg19: chr14-58734210;