12-121894821-C-T

Position:

• chr12-121894821-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002813.7(PSMD9):​c.221C>T​(p.Thr74Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00115 in 1,613,654 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0013 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: PSMD9 NM_002813.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.33

Genes affected

PSMD9 (HGNC:9567): (proteasome 26S subunit, non-ATPase 9) 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 a non-ATPase subunit of the 19S regulator. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008055031).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00129 (197/152276) while in subpopulation EAS AF= 0.0359 (186/5184). AF 95% confidence interval is 0.0317. There are 5 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD9	NM_002813.7	c.221C>T	p.Thr74Ile	missense_variant	2/6	ENST00000541212.6	NP_002804.2
PSMD9	NM_001261400.3	c.138+5827C>T		intron_variant			NP_001248329.1
PSMD9	NR_048555.3	n.288C>T		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD9	ENST00000541212.6	c.221C>T	p.Thr74Ile	missense_variant	2/6	1	NM_002813.7	ENSP00000440485	P4

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152158 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00276 AC: 689 AN: 249290 Hom.: 10 AF XY: 0.00258 AC XY: 348 AN XY: 134828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0356

Gnomad SAS exome AF: 0.000888

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.00114 AC: 1660 AN: 1461378 Hom.: 28 Cov.: 30 AF XY: 0.00113 AC XY: 820 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0370

Gnomad4 SAS exome AF: 0.000964

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152276 Hom.: 5 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74446

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0359

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000297 Hom.: 1

Bravo AF: 0.00175

ExAC AF: 0.00265 AC: 322

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0081	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.18
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.24	B;.;.
Vest4		0.76
MVP		0.40
MPC		0.25
ClinPred		0.086	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.51

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: rs2291116; hg19: chr12-122332727;