3-51958125-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001174100.2(PCBP4):c.1148C>T(p.Thr383Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000774 in 1,608,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (1 hom.)
• Consequence: PCBP4 NM_001174100.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.90

Genes affected

PCBP4 (HGNC:8652): (poly(rC) binding protein 4) 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. This gene is induced by the p53 tumor suppressor, and the encoded protein can suppress cell proliferation by inducing apoptosis and cell cycle arrest in G(2)-M. This gene's protein is found in the cytoplasm, yet it lacks the nuclear localization signals found in other subfamily members. Multiple alternatively spliced transcript variants have been described, but the full-length nature for only some has been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25248492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCBP4	NM_001174100.2	c.1148C>T	p.Thr383Ile	missense_variant	14/14	ENST00000461554.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCBP4	ENST00000461554.6	c.1148C>T	p.Thr383Ile	missense_variant	14/14	1	NM_001174100.2	P1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000277 AC: 68 AN: 245452 Hom.: 0 AF XY: 0.000249 AC XY: 33 AN XY: 132654

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000894

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000541

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.000803 AC: 1169 AN: 1455844 Hom.: 1 Cov.: 31 AF XY: 0.000765 AC XY: 554 AN XY: 724206

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.000183

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000993

Gnomad4 OTH exome AF: 0.000948

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74354

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000628 Hom.: 1

Bravo AF: 0.000563

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000239 AC: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.1148C>T (p.T383I) alteration is located in exon 14 (coding exon 12) of the PCBP4 gene. This alteration results from a C to T substitution at nucleotide position 1148, causing the threonine (T) at amino acid position 383 to be replaced by an isoleucine (I). 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	0.73
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;.;T;T;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	2.0	M;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.022	D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.47
MVP		0.64
MPC		1.3
ClinPred		0.13	T
GERP RS		5.5
Varity_R		0.14
gMVP		0.55

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: rs149099513; hg19: chr3-51992141;