17-38753246-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002795.4(PSMB3):​c.100A>C​(p.Met34Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M34V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSMB3 NM_002795.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.97
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34465963).

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>C	p.Met34Leu	missense	Exon 2 of 6	NP_002786.2
	PSMB3	NR_104194.2		n.186A>C		non_coding_transcript_exon	Exon 2 of 5
	PSMB3	NR_104195.2		n.186A>C		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>C	p.Met34Leu	missense	Exon 2 of 6	ENSP00000483688.1	P49720
	PSMB3	ENST00000931612.1		c.100A>C	p.Met34Leu	missense	Exon 2 of 6	ENSP00000601671.1
	PSMB3	ENST00000931615.1		c.100A>C	p.Met34Leu	missense	Exon 2 of 6	ENSP00000601674.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Benign	0.89
DEOGEN2	Benign	0.036	T
Eigen	Benign	0.050
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	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)
MVP		0.17
ClinPred		0.91	D
GERP RS		5.6
PromoterAI		0.0018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.75
gMVP		0.54
Mutation Taster		=88/12	polymorphism

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;