17-4796737-A-G

Variant names:

• chr17-4796737-A-G
• rs747052551
• NM_002798.3:c.112A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002798.3(PSMB6):​c.112A>G​(p.Met38Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PSMB6 NM_002798.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95

Genes affected

PSMB6 (HGNC:9543): (proteasome 20S subunit beta 6) 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. The encoded protein is a member of the proteasome B-type family, also known as the T1B family, and is a 20S core beta subunit in the proteasome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB6	NM_002798.3	c.112A>G	p.Met38Val	missense_variant	Exon 2 of 6	ENST00000270586.8	NP_002789.1
PSMB6	NM_001270481.2	c.112A>G	p.Met38Val	missense_variant	Exon 2 of 6		NP_001257410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB6	ENST00000270586.8	c.112A>G	p.Met38Val	missense_variant	Exon 2 of 6	1	NM_002798.3	ENSP00000270586.3
PSMB6	ENST00000614486.4	c.112A>G	p.Met38Val	missense_variant	Exon 2 of 6	2		ENSP00000485006.1
PSMB6	ENST00000571309.1	n.103A>G		non_coding_transcript_exon_variant	Exon 2 of 6	3		ENSP00000460811.1
PSMB6	ENST00000575079.1	n.146A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453658 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723764

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.112A>G (p.M38V) alteration is located in exon 2 (coding exon 2) of the PSMB6 gene. This alteration results from a A to G substitution at nucleotide position 112, causing the methionine (M) at amino acid position 38 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.077	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.72	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.5	.;D
REVEL	Benign	0.21
Sift	Benign	0.11	.;T
Sift4G	Benign	0.29	T;T
Polyphen		0.99	.;D
Vest4		0.84
MutPred		0.48		Gain of catalytic residue at M38 (P = 0.0877);Gain of catalytic residue at M38 (P = 0.0877);
MVP		0.52
MPC		0.53
ClinPred		0.83	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.90

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: rs747052551; hg19: chr17-4700032;