22-42596250-A-G

Variant names:

• chr22-42596250-A-G
• NM_032311.5:c.749T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032311.5(POLDIP3):​c.749T>C​(p.Leu250Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 4.22

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28979576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLDIP3	NM_032311.5	c.749T>C	p.Leu250Ser	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.749T>C	p.Leu250Ser	missense_variant	Exon 5 of 9	1	NM_032311.5	ENSP00000252115.5
ENSG00000289517	ENST00000617178.5	n.*1610T>C		non_coding_transcript_exon_variant	Exon 10 of 14	1		ENSP00000482500.2
ENSG00000289517	ENST00000617178.5	n.*1610T>C		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

Jun 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.749T>C (p.L250S) alteration is located in exon 5 (coding exon 5) of the POLDIP3 gene. This alteration results from a T to C substitution at nucleotide position 749, causing the leucine (L) at amino acid position 250 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	0.20
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	.;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T;D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.1	.;L;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.45	N;N;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.015	D;D;.
Sift4G	Uncertain	0.016	D;D;T
Polyphen		1.0	D;D;.
Vest4		0.63
MutPred		0.43		.;Loss of stability (P = 0.0152);.;
MVP		0.43
MPC		0.47
ClinPred		0.87	D
GERP RS		6.0
Varity_R		0.069
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr22-42992256;