14-35312899-T-C

Position:

• chr14-35312899-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002791.3(PSMA6):​c.428T>C​(p.Ile143Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSMA6 NM_002791.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.21

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMA6	NM_002791.3	c.428T>C	p.Ile143Thr	missense_variant	5/7	ENST00000261479.9	NP_002782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMA6	ENST00000261479.9	c.428T>C	p.Ile143Thr	missense_variant	5/7	1	NM_002791.3	ENSP00000261479.4
ENSG00000258790	ENST00000557565.1	n.*1243T>C		non_coding_transcript_exon_variant	13/15	2		ENSP00000454657.1
ENSG00000258790	ENST00000557565.1	n.*1243T>C		3_prime_UTR_variant	13/15	2		ENSP00000454657.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1439060 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716476

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.428T>C (p.I143T) alteration is located in exon 5 (coding exon 5) of the PSMA6 gene. This alteration results from a T to C substitution at nucleotide position 428, causing the isoleucine (I) at amino acid position 143 to be replaced by a threonine (T). 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	0.30
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;.;T;T;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;.;D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.0	.;.;M;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.8	N;.;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.077	T;.;T;T;T;D
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.0020	.;.;B;.;.;.
Vest4		0.72
MutPred		0.70		.;.;Loss of stability (P = 2e-04);.;.;Loss of stability (P = 2e-04);
MVP		0.41
MPC		0.93
ClinPred		0.80	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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.

Other links and lift over

hg19: chr14-35782105;