21-45913957-C-T

Variant names:

• chr21-45913957-C-T
• NM_001384156.1:c.607C>T

Variant summary

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

The NM_001384156.1(PCBP3):​c.607C>T​(p.Pro203Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCBP3 NM_001384156.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

Genes affected

PCBP3 (HGNC:8651): (poly(rC) binding protein 3) This gene encodes a member of the KH-domain protein subfamily. Proteins of this subfamily, also referred to as alpha-CPs, bind to RNA with a specificity for C-rich pyrimidine regions. Alpha-CPs play important roles in post-transcriptional activities and have different cellular distributions. The protein encoded by this gene lacks the nuclear localization signals found in other subfamily members. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2017]

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
PCBP3	NM_001384156.1	c.607C>T	p.Pro203Ser	missense_variant	Exon 12 of 18	ENST00000681687.1	NP_001371085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCBP3	ENST00000681687.1	c.607C>T	p.Pro203Ser	missense_variant	Exon 12 of 18		NM_001384156.1	ENSP00000505796.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459620 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726088

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.607C>T (p.P203S) alteration is located in exon 8 (coding exon 8) of the PCBP3 gene. This alteration results from a C to T substitution at nucleotide position 607, causing the proline (P) at amino acid position 203 to be replaced by a serine (S). 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	0.99
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;.;.;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;.
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.49	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	M;M;M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.0	D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.065	T;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.85	P;B;B;P;P
Vest4		0.73
MutPred		0.37		Loss of catalytic residue at P202 (P = 0.0123);Loss of catalytic residue at P202 (P = 0.0123);Loss of catalytic residue at P202 (P = 0.0123);.;.;
MVP		0.26
MPC		0.56
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.64
gMVP		0.76

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: chr21-47333871;