1-109411891-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002790.4(PSMA5):c.444G>C(p.Glu148Asp) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMA5 NM_002790.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.713

Genes affected

PSMA5 (HGNC:9534): (proteasome 20S subunit alpha 5) 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. Multiple alternatively spliced transcript variants encoding two distinct isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PSMA5
• BP4: Computational evidence support a benign effect (MetaRNN=0.36297506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMA5	NM_002790.4	c.444G>C	p.Glu148Asp	missense_variant	6/9	ENST00000271308.9
PSMA5	NM_001199772.2	c.270G>C	p.Glu90Asp	missense_variant	5/8
PSMA5	NM_001199773.2	c.270G>C	p.Glu90Asp	missense_variant	6/9
PSMA5	NM_001199774.2	c.270G>C	p.Glu90Asp	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMA5	ENST00000271308.9	c.444G>C	p.Glu148Asp	missense_variant	6/9	1	NM_002790.4	P1
PSMA5	ENST00000538610.5	c.270G>C	p.Glu90Asp	missense_variant	6/9	1
PSMA5	ENST00000490870.5	n.1222G>C		non_coding_transcript_exon_variant	6/9	1
PSMA5	ENST00000477897.1	n.254G>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.444G>C (p.E148D) alteration is located in exon 6 (coding exon 6) of the PSMA5 gene. This alteration results from a G to C substitution at nucleotide position 444, causing the glutamic acid (E) at amino acid position 148 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.17
Sift	Benign	0.36	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0	B;.
Vest4		0.59
MutPred		0.36		Loss of methylation at K149 (P = 0.0873);.;
MVP		0.52
MPC		1.0
ClinPred		0.28	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-109954513;