rs11542836

Variant names:

• chr19-39974363-C-T
• rs11542836
• NM_006503.4:c.392C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006503.4(PSMC4):​c.392C>T​(p.Ala131Val) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSMC4 NM_006503.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56
• Publications: 5 publications found

Genes affected

PSMC4 (HGNC:9551): (proteasome 26S subunit, ATPase 4) 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. This gene encodes a member of the triple-A family of ATPases that is a component of the 19S regulatory subunit and plays a role in 26S proteasome assembly. The encoded protein interacts with gankyrin, a liver oncoprotein, and may also play a role in Parkinson's disease through interactions with synphilin-1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMC4	NM_006503.4	c.392C>T	p.Ala131Val	missense_variant	Exon 4 of 11	ENST00000157812.7	NP_006494.1
PSMC4	NM_153001.3	c.299C>T	p.Ala100Val	missense_variant	Exon 4 of 11		NP_694546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMC4	ENST00000157812.7	c.392C>T	p.Ala131Val	missense_variant	Exon 4 of 11	1	NM_006503.4	ENSP00000157812.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.0	M;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.99	D;P
Vest4		0.81
MutPred		0.43		Gain of loop (P = 0.069);.;
MVP		0.93
MPC		2.2
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.83
gMVP		0.91
Mutation Taster		=10/90	disease causing

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: rs11542836; hg19: chr19-40480270;