2-231070095-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_002807.4(PSMD1):c.581G>A(p.Arg194Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000216 in 1,576,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PSMD1 NM_002807.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

PSMD1 (HGNC:9554): (proteasome 26S subunit, non-ATPase 1) 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. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes the largest non-ATPase subunit of the 19S regulator lid, which is responsible for substrate recognition and binding. There is evidence that this proteasome and its subunits interact with viral proteins, including those of coronaviruses. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PSMD1
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMD1	NM_002807.4	c.581G>A	p.Arg194Gln	missense_variant	6/25	ENST00000308696.11
PSMD1	NM_001191037.2	c.581G>A	p.Arg194Gln	missense_variant	6/24
PSMD1	XM_017004517.3	c.581G>A	p.Arg194Gln	missense_variant	6/18
PSMD1	NR_034059.2	n.570G>A		non_coding_transcript_exon_variant	5/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMD1	ENST00000308696.11	c.581G>A	p.Arg194Gln	missense_variant	6/25	1	NM_002807.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000401 AC: 9 AN: 224256 Hom.: 0 AF XY: 0.0000327 AC XY: 4 AN XY: 122144

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.0000776

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000399

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000469

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000183 AC: 26 AN: 1424594 Hom.: 0 Cov.: 29 AF XY: 0.0000212 AC XY: 15 AN XY: 708614

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000502

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000128

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74432

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000393 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

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

Dec 07, 2021

The c.581G>A (p.R194Q) alteration is located in exon 6 (coding exon 6) of the PSMD1 gene. This alteration results from a G to A substitution at nucleotide position 581, causing the arginine (R) at amino acid position 194 to be replaced by a glutamine (Q). 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	0.78
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;.;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	3.0	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D;D;D;D;.
REVEL	Uncertain	0.55
Sift	Benign	0.043	D;D;D;D;.
Sift4G	Uncertain	0.025	D;D;D;D;D
Polyphen		1.0	D;D;.;D;.
Vest4		0.81
MVP		0.86
MPC		0.082
ClinPred		0.84	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs371110831; hg19: chr2-231934809; COSMIC: COSV58076704;