rs14930

Variant names:

• chr14-24138797-C-A
• rs14930
• NM_006263.4:c.731C>A

Variant summary

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

The NM_006263.4(PSME1):​c.731C>A​(p.Thr244Lys) 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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSME1 NM_006263.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25
• Publications: 6 publications found

Genes affected

PSME1 (HGNC:9568): (proteasome activator subunit 1) 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. The immunoproteasome contains an alternate regulator, referred to as the 11S regulator or PA28, that replaces the 19S regulator. Three subunits (alpha, beta and gamma) of the 11S regulator have been identified. This gene encodes the alpha subunit of the 11S regulator, one of the two 11S subunits that is induced by gamma-interferon. Three alpha and three beta subunits combine to form a heterohexameric ring. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

EMC9 (HGNC:20273): (ER membrane protein complex subunit 9) Contributes to membrane insertase activity. Involved in protein insertion into ER membrane by stop-transfer membrane-anchor sequence and tail-anchored membrane protein insertion into ER membrane. Located in cytoplasm. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.14461765).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006263.4. 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
	PSME1	NM_006263.4	MANE Select	c.731C>A	p.Thr244Lys	missense	Exon 11 of 11	NP_006254.1	Q06323-1
	PSME1	NM_001281529.2		c.692C>A	p.Thr231Lys	missense	Exon 11 of 11	NP_001268458.1
	PSME1	NM_176783.3		c.*153C>A		3_prime_UTR	Exon 10 of 10	NP_788955.1	Q06323-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSME1	ENST00000206451.11	TSL:1 MANE Select	c.731C>A	p.Thr244Lys	missense	Exon 11 of 11	ENSP00000206451.6	Q06323-1
	PSME1	ENST00000967336.1		c.728C>A	p.Thr243Lys	missense	Exon 11 of 11	ENSP00000637395.1
	PSME1	ENST00000939858.1		c.725C>A	p.Thr242Lys	missense	Exon 11 of 11	ENSP00000609917.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.076	T
Eigen	Benign	0.052
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.3
PROVEAN	Benign	0.080	N
REVEL	Benign	0.067
Sift	Benign	0.19	T
Sift4G	Benign	0.22	T
Polyphen		0.84	P
Vest4		0.37
MutPred		0.17		Gain of methylation at T244 (P = 0.0093)
MVP		0.28
ClinPred		0.44	T
GERP RS		4.3
Varity_R		0.060
Mutation Taster		=85/15	polymorphism

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

dbSNP: rs14930; hg19: chr14-24608006;