22-42596275-G-A

Variant names:

• chr22-42596275-G-A
• rs1925982941
• NM_032311.5:c.724C>T

Variant summary

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

The NM_032311.5(POLDIP3):​c.724C>T​(p.Pro242Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: POLDIP3 NM_032311.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

Genes affected

POLDIP3 (HGNC:23782): (DNA polymerase delta interacting protein 3) This gene encodes an RRM (RNA recognition motif)-containing protein that participates in the regulation of translation by recruiting ribosomal protein S6 kinase beta-1 to mRNAs. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ENSG00000289517 (HGNC:):

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=0.17549995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLDIP3	NM_032311.5	c.724C>T	p.Pro242Ser	missense_variant	Exon 5 of 9	ENST00000252115.10	NP_115687.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLDIP3	ENST00000252115.10	c.724C>T	p.Pro242Ser	missense_variant	Exon 5 of 9	1	NM_032311.5	ENSP00000252115.5
ENSG00000289517	ENST00000617178.5	n.*1585C>T		non_coding_transcript_exon_variant	Exon 10 of 14	1		ENSP00000482500.2
ENSG00000289517	ENST00000617178.5	n.*1585C>T		3_prime_UTR_variant	Exon 10 of 14	1		ENSP00000482500.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.724C>T (p.P242S) alteration is located in exon 5 (coding exon 5) of the POLDIP3 gene. This alteration results from a C to T substitution at nucleotide position 724, causing the proline (P) at amino acid position 242 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	Benign	0.10
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0047	.;T;T;T
Eigen	Benign	-0.022
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	.;M;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.2	N;N;.;.
REVEL	Benign	0.058
Sift	Benign	0.075	T;T;.;.
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		0.91	P;B;.;.
Vest4		0.28
MutPred		0.30		.;Loss of sheet (P = 0.0025);.;.;
MVP		0.44
MPC		0.085
ClinPred		0.78	D
GERP RS		4.9
Varity_R		0.074
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1925982941; hg19: chr22-42992281;