17-39988707-A-C

Position:

• chr17-39988707-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002809.4(PSMD3):​c.574A>C​(p.Met192Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PSMD3 NM_002809.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19334757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD3	NM_002809.4	c.574A>C	p.Met192Leu	missense_variant	4/12	ENST00000264639.9	NP_002800.2
LOC124904000	XR_007065751.1	n.3544T>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD3	ENST00000264639.9	c.574A>C	p.Met192Leu	missense_variant	4/12	1	NM_002809.4	ENSP00000264639.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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

Sep 10, 2024

The c.574A>C (p.M192L) alteration is located in exon 4 (coding exon 4) of the PSMD3 gene. This alteration results from a A to C substitution at nucleotide position 574, causing the methionine (M) at amino acid position 192 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	0.10
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.030
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.78	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Benign	0.21	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.42		Loss of MoRF binding (P = 0.0777);
MVP		0.51
MPC		0.60
ClinPred		0.62	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.30

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: chr17-38144960;