9-120818099-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005047.4(PSMD5):ā€‹c.1322T>Cā€‹(p.Val441Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,096 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 (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

PSMD5
NM_005047.4 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.94
Variant links:
Genes affected
PSMD5 (HGNC:9563): (proteasome 26S subunit, non-ATPase 5) 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. This gene encodes a non-ATPase subunit of the 19S regulator base that functions as a chaperone protein during 26S proteasome assembly. [provided by RefSeq, Jul 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.33944178).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PSMD5NM_005047.4 linkuse as main transcriptc.1322T>C p.Val441Ala missense_variant 10/10 ENST00000210313.8 NP_005038.1 Q16401-1
PSMD5NM_001270427.2 linkuse as main transcriptc.1193T>C p.Val398Ala missense_variant 9/9 NP_001257356.1 Q16401-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PSMD5ENST00000210313.8 linkuse as main transcriptc.1322T>C p.Val441Ala missense_variant 10/101 NM_005047.4 ENSP00000210313.2 Q16401-1
PSMD5ENST00000373904.5 linkuse as main transcriptc.1193T>C p.Val398Ala missense_variant 9/92 ENSP00000363011.5 Q16401-2
PSMD5ENST00000373920.6 linkuse as main transcriptc.277-2311T>C intron_variant 5 ENSP00000363030.2 Q4VXH0

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461872
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000189

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 17, 2024The c.1322T>C (p.V441A) alteration is located in exon 10 (coding exon 10) of the PSMD5 gene. This alteration results from a T to C substitution at nucleotide position 1322, causing the valine (V) at amino acid position 441 to be replaced by an alanine (A). 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
0.25
BayesDel_addAF
Uncertain
0.022
T
BayesDel_noAF
Benign
-0.21
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
T;.
Eigen
Uncertain
0.60
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.0089
T
MetaRNN
Benign
0.34
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
2.0
M;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-2.6
D;D
REVEL
Benign
0.22
Sift
Uncertain
0.0050
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
0.82
P;.
Vest4
0.47
MutPred
0.63
Loss of sheet (P = 0.0315);.;
MVP
0.56
MPC
0.14
ClinPred
0.94
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.24
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1206294635; hg19: chr9-123580377; API