17-67341042-G-C

Variant names:

• chr17-67341042-G-C
• NM_002816.5:c.1172C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002816.5(PSMD12):​c.1172C>G​(p.Ala391Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A391V) has been classified 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: 6.64
• Publications: 0 publications found

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]

PSMD12 Gene-Disease associations (from GenCC):

• Stankiewicz-Isidor syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2387329).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMD12	NM_002816.5	c.1172C>G	p.Ala391Gly	missense_variant	Exon 11 of 11	ENST00000356126.8	NP_002807.1
PSMD12	NM_174871.4	c.1112C>G	p.Ala371Gly	missense_variant	Exon 10 of 10		NP_777360.1
PSMD12	NM_001316341.2	c.995C>G	p.Ala332Gly	missense_variant	Exon 13 of 13		NP_001303270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMD12	ENST00000356126.8	c.1172C>G	p.Ala391Gly	missense_variant	Exon 11 of 11	1	NM_002816.5	ENSP00000348442.3

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

Dec 22, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter 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	Benign	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T;.
Eigen	Benign	-0.091
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.
PhyloP100		6.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.059
Sift	Benign	0.093	T;T
Sift4G	Benign	0.092	T;T
Polyphen		0.0	B;.
Vest4		0.13
MutPred		0.44		Loss of stability (P = 0.013);.;
MVP		0.29
MPC		0.78
ClinPred		0.90	D
GERP RS		4.8
Varity_R		0.15
gMVP		0.34

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

hg19: chr17-65337158;