22-42596243-G-C

Variant names:

• chr22-42596243-G-C
• NM_032311.5:c.756C>G

Variant summary

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

The NM_032311.5(POLDIP3):​c.756C>G​(p.Asn252Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: POLDIP3 NM_032311.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

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=0.15325484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLDIP3	NM_032311.5	c.756C>G	p.Asn252Lys	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.756C>G	p.Asn252Lys	missense_variant	Exon 5 of 9	1	NM_032311.5	ENSP00000252115.5
ENSG00000289517	ENST00000617178.5	n.*1617C>G		non_coding_transcript_exon_variant	Exon 10 of 14	1		ENSP00000482500.2
ENSG00000289517	ENST00000617178.5	n.*1617C>G		3_prime_UTR_variant	Exon 10 of 14	1		ENSP00000482500.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.756C>G (p.N252K) alteration is located in exon 5 (coding exon 5) of the POLDIP3 gene. This alteration results from a C to G substitution at nucleotide position 756, causing the asparagine (N) at amino acid position 252 to be replaced by a lysine (K). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0040	.;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.031
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.61	N;N;.
REVEL	Benign	0.054
Sift	Benign	0.26	T;T;.
Sift4G	Benign	0.14	T;T;T
Polyphen		0.029	B;B;.
Vest4		0.37
MutPred		0.34		.;Gain of MoRF binding (P = 0.05);.;
MVP		0.52
MPC		0.10
ClinPred		0.32	T
GERP RS		4.6
Varity_R		0.068
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr22-42992249;