15-78546636-T-C

Position:

• chr15-78546636-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002789.6(PSMA4):​c.569T>C​(p.Leu190Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMA4 NM_002789.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

PSMA4 (HGNC:9533): (proteasome 20S subunit alpha 4) This gene encodes a core alpha subunit of the 20S proteosome, which is a highly ordered ring-shaped structure composed of four rings of 28 non-identical subunits. Proteasomes cleave peptides in an ATP- and ubiquitin-dependent manner. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMA4	NM_002789.6	c.569T>C	p.Leu190Pro	missense_variant	8/9	ENST00000044462.12	NP_002780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMA4	ENST00000044462.12	c.569T>C	p.Leu190Pro	missense_variant	8/9	1	NM_002789.6	ENSP00000044462.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Nov 11, 2024

The c.569T>C (p.L190P) alteration is located in exon 8 (coding exon 7) of the PSMA4 gene. This alteration results from a T to C substitution at nucleotide position 569, causing the leucine (L) at amino acid position 190 to be replaced by a proline (P). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	.;T;T;.;.;.;T;T;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	2.9	.;M;M;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.073	T;T;T;T;T;T;T;T;T;D
Sift4G	Benign	0.099	T;T;T;T;T;D;T;T;T;D
Polyphen		0.99	.;D;D;.;.;.;.;.;.;.
Vest4		0.90
MutPred		0.84		.;Gain of disorder (P = 0.0397);Gain of disorder (P = 0.0397);.;.;.;Gain of disorder (P = 0.0397);Gain of disorder (P = 0.0397);Gain of disorder (P = 0.0397);.;
MVP		0.67
MPC		1.0
ClinPred		0.97	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.87
gMVP		0.98

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.

Other links and lift over

hg19: chr15-78838978;