14-90272352-A-G

Variant names:

• chr14-90272352-A-G
• rs1169244113
• NM_002802.3:c.1268A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002802.3(PSMC1):​c.1268A>G​(p.Lys423Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PSMC1 NM_002802.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72
• Publications: 0 publications found

Genes affected

PSMC1 (HGNC:9547): (proteasome 26S subunit, ATPase 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. This gene encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. This subunit and a 20S core alpha subunit interact specifically with the hepatitis B virus X protein, a protein critical to viral replication. This subunit also interacts with the adenovirus E1A protein and this interaction alters the activity of the proteasome. Finally, this subunit interacts with ataxin-7, suggesting a role for the proteasome in the development of spinocerebellar ataxia type 7, a progressive neurodegenerative disorder. [provided by RefSeq, Jul 2008]

NRDE2 (HGNC:20186): (NRDE-2, necessary for RNA interference, domain containing) Involved in several processes, including RNA splicing; negative regulation of RNA catabolic process; and positive regulation of RNA export from nucleus. Located in nuclear speck and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.9473 (above the threshold of 3.09). Trascript score misZ: 5.1768 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder, neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25302374).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002802.3. 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
	PSMC1	NM_002802.3	MANE Select	c.1268A>G	p.Lys423Arg	missense	Exon 11 of 11	NP_002793.2
	NRDE2	NM_017970.4	MANE Select	c.*5984T>C		3_prime_UTR	Exon 14 of 14	NP_060440.2
	PSMC1	NM_001330212.2		c.1049A>G	p.Lys350Arg	missense	Exon 12 of 12	NP_001317141.1	P62191-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMC1	ENST00000261303.13	TSL:1 MANE Select	c.1268A>G	p.Lys423Arg	missense	Exon 11 of 11	ENSP00000261303.8	P62191-1
	NRDE2	ENST00000354366.8	TSL:1 MANE Select	c.*5984T>C		3_prime_UTR	Exon 14 of 14	ENSP00000346335.3	Q9H7Z3
	PSMC1	ENST00000906986.1		c.1265A>G	p.Lys422Arg	missense	Exon 11 of 11	ENSP00000577045.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000450 AC: 1 AN: 222428 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450422 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 721618

African (AFR) AF: 0.0000306 AC: 1 AN: 32668

American (AMR) AF: 0.0000236 AC: 1 AN: 42352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 84448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108214

Other (OTH) AF: 0.00 AC: 0 AN: 59794

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.0054	D
MutationAssessor	Benign	-0.23	N
PhyloP100		8.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.39
Sift	Benign	0.61	T
Sift4G	Benign	0.40	T
Polyphen		0.0080	B
Vest4		0.50
MutPred		0.42		Loss of ubiquitination at K423 (P = 0.0446)
MVP		0.94
MPC		1.2
ClinPred		0.48	T
GERP RS		5.8
Varity_R		0.43
gMVP		0.85
Mutation Taster		=17/83	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: rs1169244113; hg19: chr14-90738696;