rs764620445

Variant names:

• chr14-90270221-T-A
• rs764620445
• NM_002802.3:c.1057T>A

Your query was ambiguous. Multiple possible variants found:

• chr14-90270221-T-A
• chr14-90270221-T-C
• chr14-90270221-T-G

Variant summary

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

The NM_002802.3(PSMC1):​c.1057T>A​(p.Phe353Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F353L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PSMC1 NM_002802.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMC1	NM_002802.3	c.1057T>A	p.Phe353Ile	missense_variant	Exon 10 of 11	ENST00000261303.13	NP_002793.2
NRDE2	NM_017970.4	c.*8115A>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000354366.8	NP_060440.2
PSMC1	NM_001330212.2	c.838T>A	p.Phe280Ile	missense_variant	Exon 11 of 12		NP_001317141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMC1	ENST00000261303.13	c.1057T>A	p.Phe353Ile	missense_variant	Exon 10 of 11	1	NM_002802.3	ENSP00000261303.8
NRDE2	ENST00000354366	c.*8115A>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_017970.4	ENSP00000346335.3
PSMC1	ENST00000543772.2	c.838T>A	p.Phe280Ile	missense_variant	Exon 9 of 10	2		ENSP00000445147.2
PSMC1	ENST00000555787.1	n.1763T>A		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461580 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.065	N;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.59	P;.
Vest4		0.76
MutPred		0.62		Gain of methylation at K350 (P = 0.0853);.;
MVP		0.96
MPC		3.2
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs764620445; hg19: chr14-90736565;