14-35278712-C-T

Position:

• chr14-35278712-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BA1

The NM_001282234.1(PSMA6):​c.13C>T​(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0659 in 1,533,850 control chromosomes in the GnomAD database, including 7,970 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (3103 hom., cov: 32)
  • Exomes 𝑓: 0.057 (4867 hom.)
• Consequence: PSMA6 NM_001282234.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.209

Genes affected

ENSG00000258790 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a glycosylation_site O-linked (GlcNAc) serine (size 0) in uniprot entity PSA6_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0039016306).
• BP6: Variant 14-35278712-C-T is Benign according to our data. Variant chr14-35278712-C-T is described in ClinVar as [Benign]. Clinvar id is 3060375.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMA6	NM_001282234.1	c.13C>T	p.Arg5Trp	missense_variant	1/7		NP_001269163.1
PRORP-PSMA6	NR_182666.1	n.3145C>T		non_coding_transcript_exon_variant	9/15
PRORP-PSMA6	NR_182667.1	n.2967C>T		non_coding_transcript_exon_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000258790	ENST00000557565.1	n.*885C>T		non_coding_transcript_exon_variant	9/15	2		ENSP00000454657.1
ENSG00000258790	ENST00000557565.1	n.*885C>T		3_prime_UTR_variant	9/15	2		ENSP00000454657.1
PSMA6	ENST00000540871.5	c.13C>T	p.Arg5Trp	missense_variant	1/7	2		ENSP00000444844.1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22183 AN: 151830 Hom.: 3094 Cov.: 32

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.0492

Gnomad SAS AF: 0.0837

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0396

Gnomad OTH AF: 0.138

GnomAD3 exomes AF: 0.109 AC: 13919 AN: 127998 Hom.: 1498 AF XY: 0.0970 AC XY: 6799 AN XY: 70106

Gnomad AFR exome AF: 0.370

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.0682

Gnomad EAS exome AF: 0.0422

Gnomad SAS exome AF: 0.0851

Gnomad FIN exome AF: 0.0424

Gnomad NFE exome AF: 0.0421

Gnomad OTH exome AF: 0.0870

GnomAD4 exome AF: 0.0571 AC: 78858 AN: 1381902 Hom.: 4867 Cov.: 30 AF XY: 0.0564 AC XY: 38467 AN XY: 681900

Gnomad4 AFR exome AF: 0.356

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.0689

Gnomad4 EAS exome AF: 0.0422

Gnomad4 SAS exome AF: 0.0855

Gnomad4 FIN exome AF: 0.0418

Gnomad4 NFE exome AF: 0.0392

Gnomad4 OTH exome AF: 0.0752

GnomAD4 genome AF: 0.146 AC: 22235 AN: 151948 Hom.: 3103 Cov.: 32 AF XY: 0.146 AC XY: 10825 AN XY: 74290

Gnomad4 AFR AF: 0.353

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.0709

Gnomad4 EAS AF: 0.0495

Gnomad4 SAS AF: 0.0834

Gnomad4 FIN AF: 0.0490

Gnomad4 NFE AF: 0.0396

Gnomad4 OTH AF: 0.138

Alfa AF: 0.0899 Hom.: 265

Bravo AF: 0.170

TwinsUK AF: 0.0396 AC: 147

ALSPAC AF: 0.0368 AC: 142

ExAC AF: 0.0693 AC: 942

Asia WGS AF: 0.0890 AC: 310 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PSMA6-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	23
DANN	Benign	0.96
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.98	T
PROVEAN	Benign	3.5	N
REVEL	Benign	0.079
Sift	Benign	0.033	D
Sift4G	Uncertain	0.010	D
Vest4		0.095
ClinPred		0.0098	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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

Other links and lift over

dbSNP: rs17103147; hg19: chr14-35747918;