17-39986702-G-T

Position:

• chr17-39986702-G-T

Variant summary

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

The ENST00000264639.9(PSMD3):​c.539G>T​(p.Arg180Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PSMD3 ENST00000264639.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.56

Genes affected

PSMD3 (HGNC:9560): (proteasome 26S subunit, non-ATPase 3) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core 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. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase 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. This gene encodes a member of the proteasome subunit S3 family that functions as one of the non-ATPase subunits of the 19S regulator lid. Single nucleotide polymorphisms in this gene are associated with neutrophil count. [provided by RefSeq, Jul 2012]

LOC124904000 (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
PSMD3	NM_002809.4	c.539G>T	p.Arg180Leu	missense_variant	3/12	ENST00000264639.9	NP_002800.2
LOC124904000	XR_007065751.1	n.3738C>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD3	ENST00000264639.9	c.539G>T	p.Arg180Leu	missense_variant	3/12	1	NM_002809.4	ENSP00000264639	P1
PSMD3	ENST00000540504.2	c.95G>T	p.Arg32Leu	missense_variant	1/4	3		ENSP00000444980
PSMD3	ENST00000580980.1	n.19G>T		non_coding_transcript_exon_variant	1/3	2
PSMD3	ENST00000415039.7	c.*13G>T		3_prime_UTR_variant, NMD_transcript_variant	3/13	2		ENSP00000407410

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461832 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

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: 0.00000180

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

Jul 11, 2023

The c.539G>T (p.R180L) alteration is located in exon 3 (coding exon 3) of the PSMD3 gene. This alteration results from a G to T substitution at nucleotide position 539, causing the arginine (R) at amino acid position 180 to be replaced by a leucine (L). 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	0.19
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.095
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.44
Sift	Benign	0.16	T
Sift4G	Benign	0.26	T
Polyphen		0.043	B
Vest4		0.74
MutPred		0.37		Loss of disorder (P = 0.0553);
MVP		0.82
MPC		0.82
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.56

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: chr17-38142955;