12-121888899-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002813.7(PSMD9):c.43G>A(p.Ala15Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,600,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PSMD9 NM_002813.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

Genes affected

PSMD9 (HGNC:9567): (proteasome 26S subunit, non-ATPase 9) 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 a non-ATPase subunit of the 19S regulator. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02145812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMD9	NM_002813.7	c.43G>A	p.Ala15Thr	missense_variant	1/6	ENST00000541212.6
PSMD9	NM_001261400.3	c.43G>A	p.Ala15Thr	missense_variant	1/4
PSMD9	NR_048555.3	n.110G>A		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMD9	ENST00000541212.6	c.43G>A	p.Ala15Thr	missense_variant	1/6	1	NM_002813.7	P4

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152284 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000823 AC: 18 AN: 218832 Hom.: 0 AF XY: 0.0000420 AC XY: 5 AN XY: 119090

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00102

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1448262 Hom.: 0 Cov.: 29 AF XY: 0.00000834 AC XY: 6 AN XY: 719340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000383

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152402 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74530

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

ExAC AF: 0.0000746 AC: 9

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

Mar 17, 2023

The c.43G>A (p.A15T) alteration is located in exon 1 (coding exon 1) of the PSMD9 gene. This alteration results from a G to A substitution at nucleotide position 43, causing the alanine (A) at amino acid position 15 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.016	T;T;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.021	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.59	N;.;.;N
MutationTaster	Benign	0.80	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.19	N;N;N;N
REVEL	Benign	0.059
Sift	Uncertain	0.0090	D;D;D;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.0030	B;.;.;.
Vest4		0.33
MVP		0.24
MPC		0.18
ClinPred		0.14	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.14
gMVP		0.24

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: rs201195366; hg19: chr12-122326805;