chr9-120821369-G-T

Position:

chr9-120821369-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005047.4(PSMD5):c.1102C>A(p.Leu368Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,591,438 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 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: 0.000045 ( 1 hom. )

Consequence

PSMD5
NM_005047.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.99

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]

PSMD5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD5	NM_005047.4 linkuse as main transcript	c.1102C>A	p.Leu368Ile	missense_variant	8/10	ENST00000210313.8	NP_005038.1	Q16401-1
PSMD5	NM_001270427.2 linkuse as main transcript	c.973C>A	p.Leu325Ile	missense_variant	7/9		NP_001257356.1	Q16401-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PSMD5	ENST00000210313.8 linkuse as main transcript	c.1102C>A	p.Leu368Ile	missense_variant	8/10	1	NM_005047.4	ENSP00000210313.2	Q16401-1
PSMD5	ENST00000373904.5 linkuse as main transcript	c.973C>A	p.Leu325Ile	missense_variant	7/9	2		ENSP00000363011.5	Q16401-2
PSMD5	ENST00000373920.6 linkuse as main transcript	c.121C>A	p.Leu41Ile	missense_variant	2/4	5		ENSP00000363030.2	Q4VXH0

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152166

Hom.:

Cov.:

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:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000731

AC:

AN:

246108

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

133240

show subpopulations

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 SAS exome

AF:

0.000600

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1439154

Hom.:

Cov.:

AF XY:

0.0000614

AC XY:

AN XY:

717164

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:

0.000755

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74458

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:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000988

AC:

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 submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.1102C>A (p.L368I) alteration is located in exon 8 (coding exon 8) of the PSMD5 gene. This alteration results from a C to A substitution at nucleotide position 1102, causing the leucine (L) at amino acid position 368 to be replaced by an isoleucine (I). 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

0.072

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.018

.;T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.0073

MetaRNN

Benign

0.067

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.39

.;N;N

REVEL

Benign

0.079

Sift

Benign

0.21

.;T;T

Sift4G

Benign

0.087

T;T;T

Polyphen

0.042

.;B;.

Vest4

0.22, 0.25

MutPred

0.75

.;Loss of helix (P = 0.079);.;

MVP

0.26

MPC

0.096

ClinPred

0.076

GERP RS

2.9

Varity_R

0.062

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.24

Position offset: -14

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over