dbSNP rs755947684: POLDIP3:p.Gly206Cys (chr22-42599715-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032311.5(POLDIP3):c.616G>T(p.Gly206Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G206S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

POLDIP3
NM_032311.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.922

Publications

0 publications found

Variant links:

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]

POLDIP3 links:

ENSG00000289517 (HGNC:):

ENSG00000289517 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24247348).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032311.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLDIP3	NM_032311.5	MANE Select	c.616G>T	p.Gly206Cys	missense	Exon 4 of 9	NP_115687.2
POLDIP3	NM_001278657.2		c.667G>T	p.Gly223Cys	missense	Exon 4 of 9	NP_001265586.1	F6VRR5
POLDIP3	NM_178136.3		c.529G>T	p.Gly177Cys	missense	Exon 3 of 8	NP_835237.1	Q9BY77-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLDIP3	ENST00000252115.10	TSL:1 MANE Select	c.616G>T	p.Gly206Cys	missense	Exon 4 of 9	ENSP00000252115.5	Q9BY77-1
POLDIP3	ENST00000348657.6	TSL:1	c.529G>T	p.Gly177Cys	missense	Exon 3 of 8	ENSP00000252116.5	Q9BY77-2
POLDIP3	ENST00000339677.10	TSL:1	c.450+3055G>T		intron	N/A	ENSP00000343060.6	Q6R954

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457002

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725196

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:

33318

American (AMR)

AF:

0.00

AC:

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107862

Other (OTH)

AF:

0.0000166

AC:

AN:

60224

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0035

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.019

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.92

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.85

REVEL

Benign

0.069

Sift

Uncertain

0.0060

Sift4G

Benign

0.089

Polyphen

0.70

Vest4

0.40

MutPred

0.41

Gain of sheet (P = 0.0125)

MVP

0.31

MPC

0.19

ClinPred

0.52

GERP RS

2.8

Varity_R

0.15

gMVP

0.29

Mutation Taster

=86/14

polymorphism

(source)

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

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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