14-90269498-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_002802.3(PSMC1):c.983T>C(p.Ile328Thr) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMC1 NM_002802.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.99

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

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PSMC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 14-90269498-T-C is Pathogenic according to our data. Variant chr14-90269498-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1710322.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMC1	NM_002802.3	c.983T>C	p.Ile328Thr	missense_variant	9/11	ENST00000261303.13
NRDE2	NM_017970.4	c.*8838A>G		3_prime_UTR_variant	14/14	ENST00000354366.8
PSMC1	NM_001330212.2	c.764T>C	p.Ile255Thr	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMC1	ENST00000261303.13	c.983T>C	p.Ile328Thr	missense_variant	9/11	1	NM_002802.3	P1
NRDE2	ENST00000354366.8	c.*8838A>G		3_prime_UTR_variant	14/14	1	NM_017970.4	P1
PSMC1	ENST00000543772.2	c.764T>C	p.Ile255Thr	missense_variant	8/10	2
PSMC1	ENST00000555787.1	n.1040T>C		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.025	B;.
Vest4		0.94
MutPred		0.90		Gain of disorder (P = 0.0361);.;
MVP		0.98
MPC		2.4
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.87
gMVP		1.0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-90735842;