Genetic Variant NM_002791.3:c.547G>C (chr14-35313018-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002791.3(PSMA6):c.547G>C(p.Val183Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000021 in 1,427,322 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PSMA6
NM_002791.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10252619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMA6	NM_002791.3 link	c.547G>C	p.Val183Leu	missense_variant	Exon 5 of 7	ENST00000261479.9	NP_002782.1	P60900-1A0A140VK44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PSMA6	ENST00000261479.9 link	c.547G>C	p.Val183Leu	missense_variant	Exon 5 of 7	1	NM_002791.3	ENSP00000261479.4	P60900-1
ENSG00000258790	ENST00000557565.1 link	n.*1362G>C		non_coding_transcript_exon_variant	Exon 13 of 15	2		ENSP00000454657.1
ENSG00000258790	ENST00000557565.1 link	n.*1362G>C		3_prime_UTR_variant	Exon 13 of 15	2		ENSP00000454657.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1427322

Hom.:

Cov.:

AF XY:

0.00000141

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:

0.00000272

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.071

.;.;T;T;.;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.0093

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D;D;.;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.10

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.2

.;.;N;.;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

1.2

N;.;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

1.0

T;.;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

.;.;B;.;.;.

Vest4

0.28

MutPred

0.58

.;.;Loss of methylation at K182 (P = 0.038);.;.;Loss of methylation at K182 (P = 0.038);

MVP

0.23

MPC

0.64

ClinPred

0.74

GERP RS

5.6

Varity_R

0.23

gMVP

0.79

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over