14-35292367-C-T

Variant names:

• chr14-35292367-C-T
• rs2277460
• ENST00000557565.1:n.*891+13649C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001282232.1(PSMA6):​c.-395C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000917 in 1,528,254 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (23 hom.)
• Consequence: PSMA6 NM_001282232.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0100
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000946 (1302/1375990) while in subpopulation EAS AF = 0.0281 (1052/37386). AF 95% confidence interval is 0.0267. There are 23 homozygotes in GnomAdExome4. There are 623 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 100 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282232.1. 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_001282232.1		c.-395C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001269161.1	P60900-3
	PSMA6	NM_001282233.1		c.-252C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001269162.1	P60900-3
	PSMA6	NM_001282232.1		c.-395C>T		5_prime_UTR	Exon 1 of 7	NP_001269161.1	P60900-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000258790	ENST00000557565.1	TSL:2	n.*891+13649C>T		intron	N/A	ENSP00000454657.1
	PSMA6	ENST00000929332.1		c.-110C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000599391.1
	PSMA6	ENST00000929333.1		c.-110C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000599392.1

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000946 AC: 1302 AN: 1375990 Hom.: 23 Cov.: 30 AF XY: 0.000920 AC XY: 623 AN XY: 677426

African (AFR) AF: 0.0000330 AC: 1 AN: 30330

American (AMR) AF: 0.00177 AC: 58 AN: 32772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20724

East Asian (EAS) AF: 0.0281 AC: 1052 AN: 37386

South Asian (SAS) AF: 0.000407 AC: 30 AN: 73762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3730

European-Non Finnish (NFE) AF: 0.000107 AC: 115 AN: 1070702

Other (OTH) AF: 0.000815 AC: 46 AN: 56448

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000833 AC XY: 62 AN XY: 74452

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.000458 AC: 7 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0158 AC: 82 AN: 5174

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 51

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.89
PhyloP100		-0.010
PromoterAI		-0.037	Neutral
Mutation Taster		=100/0	polymorphism

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: rs2277460; hg19: chr14-35761573; COSMIC: COSV54836463; COSMIC: COSV54836463;