17-38753246-A-T

Variant names:

• chr17-38753246-A-T
• rs4907
• NM_002795.4:c.100A>T

Variant summary

Our verdict is Benign. The variant received -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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M34V) has been classified as Uncertain significance.

• 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
• Publications: 30 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002795.4. 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
	PSMB3	NM_002795.4	MANE Select	c.100A>T	p.Met34Leu	missense	Exon 2 of 6	NP_002786.2
	PSMB3	NR_104194.2		n.186A>T		non_coding_transcript_exon	Exon 2 of 5
	PSMB3	NR_104195.2		n.186A>T		non_coding_transcript_exon	Exon 2 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB3	ENST00000619426.5	TSL:1 MANE Select	c.100A>T	p.Met34Leu	missense	Exon 2 of 6	ENSP00000483688.1	P49720
	PSMB3	ENST00000931612.1		c.100A>T	p.Met34Leu	missense	Exon 2 of 6	ENSP00000601671.1
	PSMB3	ENST00000931615.1		c.100A>T	p.Met34Leu	missense	Exon 2 of 6	ENSP00000601674.1

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

GnomAD2 exomes AF: 0.146 AC: 36724 AN: 251328 AF XY: 0.135

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 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

African (AFR) AF: 0.0498 AC: 1667 AN: 33480

American (AMR) AF: 0.356 AC: 15923 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0601 AC: 1572 AN: 26136

East Asian (EAS) AF: 0.227 AC: 9025 AN: 39700

South Asian (SAS) AF: 0.0921 AC: 7945 AN: 86258

European-Finnish (FIN) AF: 0.147 AC: 7839 AN: 53414

Middle Eastern (MID) AF: 0.0459 AC: 265 AN: 5768

European-Non Finnish (NFE) AF: 0.0944 AC: 104927 AN: 1112008

Other (OTH) AF: 0.100 AC: 6043 AN: 60396

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

African (AFR) AF: 0.0515 AC: 2138 AN: 41538

American (AMR) AF: 0.234 AC: 3582 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 187 AN: 3470

East Asian (EAS) AF: 0.259 AC: 1339 AN: 5172

South Asian (SAS) AF: 0.101 AC: 486 AN: 4822

European-Finnish (FIN) AF: 0.159 AC: 1681 AN: 10584

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0975 AC: 6634 AN: 68008

Other (OTH) AF: 0.0889 AC: 188 AN: 2114

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 v4.9

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
Eigen	Benign	0.050
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N
PhyloP100		7.0
PrimateAI	Uncertain	0.79	T
Sift4G	Benign	0.069	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
PromoterAI		0.032	Neutral
Varity_R		0.75
gMVP		0.54
Mutation Taster		=88/12	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: rs4907; hg19: chr17-36909499;