17-67340913-GA-AT

Position:

• chr17-67340913-GA-AT

Variant summary

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

The NM_002816.5(PSMD12):​c.1300_1301delTCinsAT​(p.Ser434Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.53

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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD12	NM_002816.5	c.1300_1301delTCinsAT	p.Ser434Ile	missense_variant		ENST00000356126.8	NP_002807.1
PSMD12	NM_174871.4	c.1240_1241delTCinsAT	p.Ser414Ile	missense_variant			NP_777360.1
PSMD12	NM_001316341.2	c.1123_1124delTCinsAT	p.Ser375Ile	missense_variant			NP_001303270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD12	ENST00000356126.8	c.1300_1301delTCinsAT	p.Ser434Ile	missense_variant		1	NM_002816.5	ENSP00000348442.3
PSMD12	ENST00000584008.5	n.*1455_*1456delTCinsAT		non_coding_transcript_exon_variant	13/13	1		ENSP00000462525.1
PSMD12	ENST00000584008.5	n.*1455_*1456delTCinsAT		3_prime_UTR_variant	13/13	1		ENSP00000462525.1
PSMD12	ENST00000357146.4	c.1240_1241delTCinsAT	p.Ser414Ile	missense_variant		2		ENSP00000349667.4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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

Jun 26, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports 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

Splicing

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: chr17-65337029;