21-45909438-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001384156.1(PCBP3):c.423T>C(p.Cys141=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 1,612,578 control chromosomes in the GnomAD database, including 425,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.78 (46927 hom., cov: 34)
  • Exomes 𝑓: 0.72 (378604 hom.)
• Consequence: PCBP3 NM_001384156.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.128

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-45909438-T-C is Benign according to our data. Variant chr21-45909438-T-C is described in ClinVar as [Benign]. Clinvar id is 3059228.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.128 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCBP3	NM_001384156.1	c.423T>C	p.Cys141=	synonymous_variant	10/18	ENST00000681687.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCBP3	ENST00000681687.1	c.423T>C	p.Cys141=	synonymous_variant	10/18		NM_001384156.1	P4

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118059 AN: 152032 Hom.: 46878 Cov.: 34

Gnomad AFR AF: 0.924

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.883

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.838

Gnomad NFE AF: 0.686

Gnomad OTH AF: 0.774

GnomAD3 exomes AF: 0.767 AC: 191008 AN: 248872 Hom.: 74771 AF XY: 0.765 AC XY: 103303 AN XY: 135054

Gnomad AFR exome AF: 0.930

Gnomad AMR exome AF: 0.825

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.997

Gnomad SAS exome AF: 0.866

Gnomad FIN exome AF: 0.680

Gnomad NFE exome AF: 0.686

Gnomad OTH exome AF: 0.750

GnomAD4 exome AF: 0.715 AC: 1044894 AN: 1460428 Hom.: 378604 Cov.: 43 AF XY: 0.719 AC XY: 522507 AN XY: 726538

Gnomad4 AFR exome AF: 0.937

Gnomad4 AMR exome AF: 0.819

Gnomad4 ASJ exome AF: 0.719

Gnomad4 EAS exome AF: 0.995

Gnomad4 SAS exome AF: 0.862

Gnomad4 FIN exome AF: 0.683

Gnomad4 NFE exome AF: 0.682

Gnomad4 OTH exome AF: 0.748

GnomAD4 genome AF: 0.777 AC: 118165 AN: 152150 Hom.: 46927 Cov.: 34 AF XY: 0.778 AC XY: 57837 AN XY: 74384

Gnomad4 AFR AF: 0.924

Gnomad4 AMR AF: 0.759

Gnomad4 ASJ AF: 0.727

Gnomad4 EAS AF: 0.995

Gnomad4 SAS AF: 0.882

Gnomad4 FIN AF: 0.685

Gnomad4 NFE AF: 0.686

Gnomad4 OTH AF: 0.776

Alfa AF: 0.716 Hom.: 10491

Bravo AF: 0.789

Asia WGS AF: 0.949 AC: 3300 AN: 3478

EpiCase AF: 0.690

EpiControl AF: 0.695

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PCBP3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.9
Dann	Benign	0.49

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: rs2277812; hg19: chr21-47329352; COSMIC: COSV68407953; COSMIC: COSV68407953;