14-58270425-A-G

Position:

chr14-58270425-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002788.4(PSMA3):c.598A>G(p.Ile200Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,613,446 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I200T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

PSMA3
NM_002788.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.81

Variant links:

Genes affected

PSMA3 (HGNC:9532): (proteasome 20S subunit alpha 3) 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. Two alternative transcripts encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

PSMA3 links:

PSMA3-AS1 (HGNC:26445): (PSMA3 antisense RNA 1)

PSMA3-AS1 links:

ARMH4 (HGNC:19846): (armadillo like helical domain containing 4) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARMH4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.010875553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMA3	NM_002788.4 linkuse as main transcript	c.598A>G	p.Ile200Val	missense_variant	9/11	ENST00000216455.9
PSMA3-AS1	NR_029435.1 linkuse as main transcript	n.414-3032T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMA3	ENST00000216455.9 linkuse as main transcript	c.598A>G	p.Ile200Val	missense_variant	9/11	1	NM_002788.4	P4	P25788-1
PSMA3-AS1	ENST00000554360.5 linkuse as main transcript	n.447-3032T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000251

AC:

AN:

251046

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135710

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:

0.00

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000150

AC:

219

AN:

1461106

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

121

AN XY:

726876

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00212

Gnomad4 NFE exome

AF:

0.0000738

Gnomad4 OTH exome

AF:

0.000365

GnomAD4 genome

AF:

0.000361

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000154

Hom.:

Bravo

AF:

0.000215

ExAC

AF:

0.000305

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3476

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.598A>G (p.I200V) alteration is located in exon 9 (coding exon 9) of the PSMA3 gene. This alteration results from a A to G substitution at nucleotide position 598, causing the isoleucine (I) at amino acid position 200 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 200 of the PSMA3 protein (p.Ile200Val). This variant is present in population databases (rs200984115, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PSMA3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1443450). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.084

T;.;T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.013

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Benign

0.0042

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.41

N;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.29

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.85

T;T;T;T

Sift4G

Benign

0.40

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.63

MVP

0.43

MPC

0.016

ClinPred

0.082

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

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

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