rs777406809

Variant names:

• chr14-35317256-A-G
• rs777406809
• NM_002791.3:c.691A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002791.3(PSMA6):​c.691A>G​(p.Thr231Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000616 in 1,460,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: PSMA6 NM_002791.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31
• Publications: 1 publications found

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]

ENSG00000258790 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24388537).
• BS2: High AC in GnomAdExome4 at 90 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002791.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMA6	NM_002791.3	MANE Select	c.691A>G	p.Thr231Ala	missense	Exon 7 of 7	NP_002782.1	P60900-1
	PSMA6	NM_001282234.1		c.634A>G	p.Thr212Ala	missense	Exon 7 of 7	NP_001269163.1	P60900-2
	PSMA6	NM_001282232.1		c.454A>G	p.Thr152Ala	missense	Exon 7 of 7	NP_001269161.1	P60900-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMA6	ENST00000261479.9	TSL:1 MANE Select	c.691A>G	p.Thr231Ala	missense	Exon 7 of 7	ENSP00000261479.4	P60900-1
	ENSG00000258790	ENST00000557565.1	TSL:2	n.*1506A>G		non_coding_transcript_exon	Exon 15 of 15	ENSP00000454657.1
	ENSG00000258790	ENST00000557565.1	TSL:2	n.*1506A>G		3_prime_UTR	Exon 15 of 15	ENSP00000454657.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251300 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1460758 Hom.: 0 Cov.: 30 AF XY: 0.0000619 AC XY: 45 AN XY: 726788

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 0.0000792 AC: 88 AN: 1111304

Other (OTH) AF: 0.0000331 AC: 2 AN: 60332

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.019	D
Polyphen		0.0	B
Vest4		0.092
MutPred		0.39		Loss of ubiquitination at K226 (P = 0.1151)
MVP		0.50
MPC		0.63
ClinPred		0.29	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.58
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs777406809; hg19: chr14-35786462;