chr17-67340906-C-T

Position:

• chr17-67340906-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002816.5(PSMD12):​c.1308G>A​(p.Met436Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSMD12 NM_002816.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

Genes affected

PSMD12 (HGNC:9557): (proteasome 26S subunit, non-ATPase 12) 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. A pseudogene has been identified on chromosome 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD12	NM_002816.5	c.1308G>A	p.Met436Ile	missense_variant	11/11	ENST00000356126.8	NP_002807.1
PSMD12	NM_174871.4	c.1248G>A	p.Met416Ile	missense_variant	10/10		NP_777360.1
PSMD12	NM_001316341.2	c.1131G>A	p.Met377Ile	missense_variant	13/13		NP_001303270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD12	ENST00000356126.8	c.1308G>A	p.Met436Ile	missense_variant	11/11	1	NM_002816.5	ENSP00000348442.3
PSMD12	ENST00000584008.5	n.*1463G>A		non_coding_transcript_exon_variant	13/13	1		ENSP00000462525.1
PSMD12	ENST00000584008.5	n.*1463G>A		3_prime_UTR_variant	13/13	1		ENSP00000462525.1
PSMD12	ENST00000357146.4	c.1248G>A	p.Met416Ile	missense_variant	10/10	2		ENSP00000349667.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.95	P;.
Vest4		0.72
MutPred		0.58		Loss of ubiquitination at K431 (P = 0.0573);.;
MVP		0.73
MPC		0.83
ClinPred		0.98	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-65337022; COSMIC: COSV62065157; COSMIC: COSV62065157;