13-19751448-G-A

Variant names:

• chr13-19751448-G-A
• rs1325365259
• NM_001354909.2:c.790C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001354909.2(PSPC1):​c.790C>T​(p.Arg264Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,368,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: PSPC1 NM_001354909.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.11

Genes affected

PSPC1 (HGNC:20320): (paraspeckle component 1) This gene encodes a nucleolar protein that localizes to punctate subnuclear structures that occur close to splicing speckles, known as paraspeckles. These paraspeckles are composed of RNA-protein structures that include a non-coding RNA, NEAT1/Men epsilon/beta, and the Drosophila Behavior Human Splicing family of proteins, which include the product of this gene and the P54NRB/NONO and PSF/SFPQ proteins. Paraspeckles may function in the control of gene expression via an RNA nuclear retention mechanism. The protein encoded by this gene is found in paraspeckles in transcriptionally active cells, but it localizes to unique cap structures at the nucleolar periphery when RNA polymerase II transcription is inhibited, or during telophase. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene, which is also located on chromosome 13, has been identified. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSPC1	NM_001354909.2	c.790C>T	p.Arg264Cys	missense_variant	Exon 4 of 9	ENST00000338910.9	NP_001341838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSPC1	ENST00000338910.9	c.790C>T	p.Arg264Cys	missense_variant	Exon 4 of 9	1	NM_001354909.2	ENSP00000343966.4
PSPC1	ENST00000471658.5	n.790C>T		non_coding_transcript_exon_variant	Exon 4 of 8	1		ENSP00000436038.1
PSPC1	ENST00000619300.4	c.790C>T	p.Arg264Cys	missense_variant	Exon 5 of 10	5		ENSP00000481916.1
PSPC1	ENST00000492741.5	n.790C>T		non_coding_transcript_exon_variant	Exon 4 of 8	2		ENSP00000435921.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1368814 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 677072

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: 0.00000280

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.790C>T (p.R264C) alteration is located in exon 5 (coding exon 4) of the PSPC1 gene. This alteration results from a C to T substitution at nucleotide position 790, causing the arginine (R) at amino acid position 264 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.1	D;.
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.50
MutPred		0.58		Gain of catalytic residue at P263 (P = 2e-04);Gain of catalytic residue at P263 (P = 2e-04);
MVP		0.49
MPC		2.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.69

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: rs1325365259; hg19: chr13-20325588;