14-35313018-G-A

Position:

chr14-35313018-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002791.3(PSMA6):c.547G>A(p.Val183Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000823 in 1,579,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

PSMA6
NM_002791.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.80

Variant links:

Genes affected

PSMA6 (HGNC:9535): (proteasome 20S subunit alpha 6) 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. Multiple transcript variants encoding several different isoforms have been found for this gene. A pseudogene has been identified on the Y chromosome. [provided by RefSeq, Aug 2013]

PSMA6 links:

ENSG00000258790 (HGNC:):

ENSG00000258790 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.179647).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMA6	NM_002791.3 linkuse as main transcript	c.547G>A	p.Val183Met	missense_variant	5/7	ENST00000261479.9	NP_002782.1	P60900-1A0A140VK44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PSMA6	ENST00000261479.9 linkuse as main transcript	c.547G>A	p.Val183Met	missense_variant	5/7	1	NM_002791.3	ENSP00000261479.4	P60900-1
ENSG00000258790	ENST00000557565.1 linkuse as main transcript	n.*1362G>A		non_coding_transcript_exon_variant	13/15	2		ENSP00000454657.1
ENSG00000258790	ENST00000557565.1 linkuse as main transcript	n.*1362G>A		3_prime_UTR_variant	13/15	2		ENSP00000454657.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152036

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000139

AC:

AN:

215492

Hom.:

AF XY:

0.00000850

AC XY:

AN XY:

117626

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:

0.00

Gnomad NFE exome

AF:

0.0000291

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000841

AC:

AN:

1427322

Hom.:

Cov.:

AF XY:

0.00000422

AC XY:

AN XY:

710202

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:

0.00000907

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74282

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

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

Apr 18, 2023

The c.547G>A (p.V183M) alteration is located in exon 5 (coding exon 5) of the PSMA6 gene. This alteration results from a G to A substitution at nucleotide position 547, causing the valine (V) at amino acid position 183 to be replaced by a methionine (M). 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

0.26

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.085

.;.;T;T;.;T

Eigen

Benign

-0.0073

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;D;.;D

M_CAP

Benign

0.0094

MetaRNN

Benign

0.18

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.93

.;.;L;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.45

N;.;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.41

T;.;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T;T

Polyphen

0.011

.;.;B;.;.;.

Vest4

0.44

MutPred

0.52

.;.;Loss of methylation at K182 (P = 0.0185);.;.;Loss of methylation at K182 (P = 0.0185);

MVP

0.40

MPC

0.65

ClinPred

0.25

GERP RS

5.6

Varity_R

0.20

gMVP

0.76

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