12-121888906-T-C

Position:

• chr12-121888906-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002813.7(PSMD9):​c.50T>C​(p.Val17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 1,596,832 control chromosomes in the GnomAD database, including 591,063 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 0.84 (54241 hom., cov: 36)
  • Exomes 𝑓: 0.86 (536822 hom.)
• Consequence: PSMD9 NM_002813.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.148

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]

ENSG00000256950 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.049505E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD9	NM_002813.7	c.50T>C	p.Val17Ala	missense_variant	1/6	ENST00000541212.6	NP_002804.2
PSMD9	NM_001261400.3	c.50T>C	p.Val17Ala	missense_variant	1/4		NP_001248329.1
PSMD9	NR_048555.3	n.117T>C		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD9	ENST00000541212.6	c.50T>C	p.Val17Ala	missense_variant	1/6	1	NM_002813.7	ENSP00000440485.1
ENSG00000256950	ENST00000546333.1	n.50T>C		non_coding_transcript_exon_variant	1/4	5		ENSP00000477146.1

Frequencies

GnomAD3 genomes AF: 0.843 AC: 128358 AN: 152184 Hom.: 54201 Cov.: 36

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.868

Gnomad OTH AF: 0.851

GnomAD3 exomes AF: 0.837 AC: 182638 AN: 218164 Hom.: 76781 AF XY: 0.843 AC XY: 100011 AN XY: 118686

Gnomad AFR exome AF: 0.834

Gnomad AMR exome AF: 0.723

Gnomad ASJ exome AF: 0.906

Gnomad EAS exome AF: 0.871

Gnomad SAS exome AF: 0.842

Gnomad FIN exome AF: 0.783

Gnomad NFE exome AF: 0.869

Gnomad OTH exome AF: 0.853

GnomAD4 exome AF: 0.861 AC: 1244096 AN: 1444530 Hom.: 536822 Cov.: 64 AF XY: 0.862 AC XY: 617851 AN XY: 717118

Gnomad4 AFR exome AF: 0.834

Gnomad4 AMR exome AF: 0.728

Gnomad4 ASJ exome AF: 0.905

Gnomad4 EAS exome AF: 0.851

Gnomad4 SAS exome AF: 0.840

Gnomad4 FIN exome AF: 0.780

Gnomad4 NFE exome AF: 0.871

Gnomad4 OTH exome AF: 0.866

GnomAD4 genome AF: 0.843 AC: 128452 AN: 152302 Hom.: 54241 Cov.: 36 AF XY: 0.838 AC XY: 62423 AN XY: 74466

Gnomad4 AFR AF: 0.834

Gnomad4 AMR AF: 0.781

Gnomad4 ASJ AF: 0.910

Gnomad4 EAS AF: 0.865

Gnomad4 SAS AF: 0.844

Gnomad4 FIN AF: 0.772

Gnomad4 NFE AF: 0.868

Gnomad4 OTH AF: 0.853

Alfa AF: 0.865 Hom.: 129841

Bravo AF: 0.844

TwinsUK AF: 0.879 AC: 3260

ALSPAC AF: 0.880 AC: 3391

ESP6500AA AF: 0.836 AC: 3675

ESP6500EA AF: 0.873 AC: 7495

ExAC AF: 0.825 AC: 98411

Asia WGS AF: 0.862 AC: 2995 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.51
DANN	Benign	0.58
DEOGEN2	Benign	0.0084	T;T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.099	T;T;T;T
MetaRNN	Benign	7.0e-7	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N;.;.;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.52	N;N;N;N
REVEL	Benign	0.013
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.018
MPC		0.22
ClinPred		0.0027	T
GERP RS		-0.45
Varity_R		0.016
gMVP		0.14

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: rs2230681; hg19: chr12-122326812; COSMIC: COSV55838997; COSMIC: COSV55838997;