9-120842818-G-C

Position:

• chr9-120842818-G-C

Variant summary

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

The NM_005047.4(PSMD5):​c.92C>G​(p.Ala31Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000216 in 1,611,890 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: PSMD5 NM_005047.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.13

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]

CUTALP (HGNC:27367): (cutA divalent cation tolerance like, pseudogene)

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=0.025264293).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD5	NM_005047.4	c.92C>G	p.Ala31Gly	missense_variant	1/10	ENST00000210313.8	NP_005038.1
PSMD5	NM_001270427.2	c.92C>G	p.Ala31Gly	missense_variant	1/9		NP_001257356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD5	ENST00000210313.8	c.92C>G	p.Ala31Gly	missense_variant	1/10	1	NM_005047.4	ENSP00000210313	P1
CUTALP	ENST00000589026.5	n.144-2175G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152270 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000259 AC: 63 AN: 243542 Hom.: 0 AF XY: 0.000248 AC XY: 33 AN XY: 133264

Gnomad AFR exome AF: 0.000795

Gnomad AMR exome AF: 0.000846

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000146

Gnomad OTH exome AF: 0.000838

GnomAD4 exome AF: 0.000186 AC: 272 AN: 1459502 Hom.: 1 Cov.: 31 AF XY: 0.000176 AC XY: 128 AN XY: 726128

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.000986

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000386

Gnomad4 NFE exome AF: 0.000126

Gnomad4 OTH exome AF: 0.000664

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152388 Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74524

Gnomad4 AFR AF: 0.000793

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000290 Hom.: 0

Bravo AF: 0.000691

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000223 AC: 27

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2024

The c.92C>G (p.A31G) alteration is located in exon 1 (coding exon 1) of the PSMD5 gene. This alteration results from a C to G substitution at nucleotide position 92, causing the alanine (A) at amino acid position 31 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	0.66	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Benign	0.12
Sift	Benign	0.034	D;D;.
Sift4G	Uncertain	0.032	D;D;T
Polyphen		0.48	P;.;.
Vest4		0.24
MVP		0.53
MPC		0.20
ClinPred		0.091	T
GERP RS		4.5
Varity_R		0.23
gMVP		0.11

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: rs151222283; hg19: chr9-123605096;