rs74421874

Variant names:

• chr12-121902546-G-A
• rs74421874
• NM_002813.7:c.454-460G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002813.7(PSMD9):​c.454-460G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 166,040 control chromosomes in the GnomAD database, including 6,649 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.

• Frequency:
  • Genomes: 𝑓 0.25 (5924 hom., cov: 32)
  • Exomes 𝑓: 0.31 (725 hom.)
• Consequence: PSMD9 NM_002813.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.910
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002813.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMD9	NM_002813.7	MANE Select	c.454-460G>A		intron	N/A	NP_002804.2
	PSMD9	NM_001261400.3		c.139-460G>A		intron	N/A	NP_001248329.1	O00233-3
	PSMD9	NR_048555.3		n.309-460G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMD9	ENST00000541212.6	TSL:1 MANE Select	c.454-460G>A		intron	N/A	ENSP00000440485.1	O00233-1
	PSMD9	ENST00000537407.5	TSL:1	n.454-460G>A		intron	N/A	ENSP00000445058.1	O00233-2
	ENSG00000256950	ENST00000546333.1	TSL:5	n.242-460G>A		intron	N/A	ENSP00000477146.1	F5H7X1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37906 AN: 152004 Hom.: 5918 Cov.: 32

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.270

GnomAD4 exome AF: 0.314 AC: 4374 AN: 13918 Hom.: 725 Cov.: 0 AF XY: 0.310 AC XY: 2276 AN XY: 7352

African (AFR) AF: 0.0532 AC: 15 AN: 282

American (AMR) AF: 0.364 AC: 676 AN: 1856

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 64 AN: 186

East Asian (EAS) AF: 0.522 AC: 351 AN: 672

South Asian (SAS) AF: 0.302 AC: 516 AN: 1706

European-Finnish (FIN) AF: 0.307 AC: 105 AN: 342

Middle Eastern (MID) AF: 0.250 AC: 14 AN: 56

European-Non Finnish (NFE) AF: 0.298 AC: 2406 AN: 8070

Other (OTH) AF: 0.303 AC: 227 AN: 748

GnomAD4 genome AF: 0.249 AC: 37919 AN: 152122 Hom.: 5924 Cov.: 32 AF XY: 0.255 AC XY: 18954 AN XY: 74336

African (AFR) AF: 0.0640 AC: 2660 AN: 41532

American (AMR) AF: 0.332 AC: 5065 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1040 AN: 3472

East Asian (EAS) AF: 0.509 AC: 2630 AN: 5162

South Asian (SAS) AF: 0.340 AC: 1642 AN: 4834

European-Finnish (FIN) AF: 0.331 AC: 3490 AN: 10554

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.300 AC: 20364 AN: 67990

Other (OTH) AF: 0.274 AC: 579 AN: 2114

Alfa AF: 0.279 Hom.: 1453

Bravo AF: 0.243

Asia WGS AF: 0.405 AC: 1404 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.64
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74421874; hg19: chr12-122340452;