rs1114167442

Variant names:

• chr17-67350267-G-A
• rs1114167442
• NM_002816.5:c.367C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-67350267-G-A
• chr17-67350267-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002816.5(PSMD12):​c.367C>T​(p.Arg123*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMD12 NM_002816.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.91
• Publications: 2 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-67350267-G-A is Pathogenic according to our data. Variant chr17-67350267-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 427779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002816.5. 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
	PSMD12	NM_002816.5	MANE Select	c.367C>T	p.Arg123*	stop_gained	Exon 4 of 11	NP_002807.1
	PSMD12	NM_174871.4		c.307C>T	p.Arg103*	stop_gained	Exon 3 of 10	NP_777360.1
	PSMD12	NM_001316341.2		c.190C>T	p.Arg64*	stop_gained	Exon 6 of 13	NP_001303270.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMD12	ENST00000356126.8	TSL:1 MANE Select	c.367C>T	p.Arg123*	stop_gained	Exon 4 of 11	ENSP00000348442.3
	PSMD12	ENST00000584008.5	TSL:1	n.*522C>T		non_coding_transcript_exon	Exon 6 of 13	ENSP00000462525.1
	PSMD12	ENST00000584289.5	TSL:1	n.416C>T		non_coding_transcript_exon	Exon 4 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Stankiewicz-Isidor syndrome (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		2.9
Vest4		0.45
GERP RS		3.9
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1114167442; hg19: chr17-65346383; COSMIC: COSV62065273; COSMIC: COSV62065273;