Genetic Variant PCBP3:c.676-6_676-3dupCTCT (chr21-45917570-G-GTCTC) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001384156.1(PCBP3):c.676-6_676-3dupCTCT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,401,216 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PCBP3
NM_001384156.1 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.93

Publications

0 publications found

Variant links:

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]

PCBP3 links:

ENSG00000280604 (HGNC:):

ENSG00000280604 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03763441 fraction of the gene. Cryptic splice site detected, with MaxEntScore 15, offset of 0 (no position change), new splice context is: ctctctctctctctctctAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384156.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCBP3	NM_001384156.1	MANE Select	c.676-6_676-3dupCTCT	splice_acceptor intron	N/A	NP_001371085.1	P57721-1
PCBP3	NM_001348240.2		c.745-6_745-3dupCTCT	splice_acceptor intron	N/A	NP_001335169.1
PCBP3	NM_001382279.1		c.745-6_745-3dupCTCT	splice_acceptor intron	N/A	NP_001369208.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCBP3	ENST00000681687.1	MANE Select	c.676-18_676-17insTCTC	intron	N/A	ENSP00000505796.1	P57721-1
PCBP3	ENST00000400304.1	TSL:1	c.649-18_649-17insTCTC	intron	N/A	ENSP00000383159.1	E9PFP8
PCBP3	ENST00000400308.5	TSL:1	c.601-18_601-17insTCTC	intron	N/A	ENSP00000383163.1	P57721-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1401216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696346

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32022

American (AMR)

AF:

0.00

AC:

AN:

42060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24880

East Asian (EAS)

AF:

0.00

AC:

AN:

38058

South Asian (SAS)

AF:

0.00

AC:

AN:

81256

European-Finnish (FIN)

AF:

0.0000196

AC:

AN:

51060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1068510

Other (OTH)

AF:

0.00

AC:

AN:

57848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over