rs4907

chr17-38753246-A-T

Variant summary

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

The NM_002795.4(PSMB3):c.100A>T(p.Met34Leu) variant causes a missense change. The variant allele was found at a frequency of 0.106 in 1,614,070 control chromosomes in the GnomAD database, including 11,826 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 0.11 (1275 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10551 hom.)
• Consequence: PSMB3 NM_002795.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.97

Genes affected

PSMB3 (HGNC:9540): (proteasome 20S subunit beta 3) The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure 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. 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 member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. The 26 S proteasome may be involved in trinucleotide repeat expansion, a phenomenon which is associated with many hereditary neurological diseases. Pseudogenes have been identified on chromosomes 2 and 12. Alternative splicing results in multiple transcript variants [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015499294).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMB3	NM_002795.4	c.100A>T	p.Met34Leu	missense_variant	2/6	ENST00000619426.5
PSMB3	NR_104194.2	n.186A>T		non_coding_transcript_exon_variant	2/5
PSMB3	NR_104195.2	n.186A>T		non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB3	ENST00000619426.5	c.100A>T	p.Met34Leu	missense_variant	2/6	1	NM_002795.4	P1
PSMB3	ENST00000610434.4	c.91A>T	p.Met31Leu	missense_variant	2/4	3
PSMB3	ENST00000620309.4	c.100A>T	p.Met34Leu	missense_variant, NMD_transcript_variant	2/5	2
PSMB3	ENST00000613870.4	c.100A>T	p.Met34Leu	missense_variant, NMD_transcript_variant	2/6	3

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16291 AN: 152076 Hom.: 1276 Cov.: 32

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0976

Gnomad OTH AF: 0.0899

GnomAD3 exomes AF: 0.146 AC: 36724 AN: 251328 Hom.: 4288 AF XY: 0.135 AC XY: 18299 AN XY: 135890

Gnomad AFR exome AF: 0.0530

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.0620

Gnomad EAS exome AF: 0.272

Gnomad SAS exome AF: 0.0926

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.0938

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.106 AC: 155206 AN: 1461876 Hom.: 10551 Cov.: 33 AF XY: 0.104 AC XY: 75881 AN XY: 727240

Gnomad4 AFR exome AF: 0.0498

Gnomad4 AMR exome AF: 0.356

Gnomad4 ASJ exome AF: 0.0601

Gnomad4 EAS exome AF: 0.227

Gnomad4 SAS exome AF: 0.0921

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.0944

Gnomad4 OTH exome AF: 0.100

GnomAD4 genome AF: 0.107 AC: 16292 AN: 152194 Hom.: 1275 Cov.: 32 AF XY: 0.112 AC XY: 8346 AN XY: 74392

Gnomad4 AFR AF: 0.0515

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.0539

Gnomad4 EAS AF: 0.259

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.0975

Gnomad4 OTH AF: 0.0889

Alfa AF: 0.0965 Hom.: 245

Bravo AF: 0.112

TwinsUK AF: 0.0871 AC: 323

ALSPAC AF: 0.101 AC: 391

ESP6500AA AF: 0.0540 AC: 238

ESP6500EA AF: 0.0942 AC: 810

ExAC AF: 0.133 AC: 16169

Asia WGS AF: 0.160 AC: 555 AN: 3478

EpiCase AF: 0.0871

EpiControl AF: 0.0829

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Benign	0.94
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	0.050
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N;.
MutationTaster	Benign	0.00057	P
PrimateAI	Uncertain	0.79	T
Sift4G	Benign	0.069	T;T
Polyphen		0.0	B;.
Vest4		0.13
MutPred		0.13		Loss of MoRF binding (P = 0.0956);.;
ClinPred		0.020	T
GERP RS		5.6
Varity_R		0.75
gMVP		0.54

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: rs4907; hg19: chr17-36909499;