22-42599715-C-G

Variant names:

• chr22-42599715-C-G
• rs755947684
• NM_032311.5:c.616G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032311.5(POLDIP3):​c.616G>C​(p.Gly206Arg) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.922
• Publications: 0 publications found

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

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=0.17875692).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLDIP3	NM_032311.5	MANE Select	c.616G>C	p.Gly206Arg	missense	Exon 4 of 9	NP_115687.2
	POLDIP3	NM_001278657.2		c.667G>C	p.Gly223Arg	missense	Exon 4 of 9	NP_001265586.1	F6VRR5
	POLDIP3	NM_178136.3		c.529G>C	p.Gly177Arg	missense	Exon 3 of 8	NP_835237.1	Q9BY77-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLDIP3	ENST00000252115.10	TSL:1 MANE Select	c.616G>C	p.Gly206Arg	missense	Exon 4 of 9	ENSP00000252115.5	Q9BY77-1
	POLDIP3	ENST00000348657.6	TSL:1	c.529G>C	p.Gly177Arg	missense	Exon 3 of 8	ENSP00000252116.5	Q9BY77-2
	POLDIP3	ENST00000339677.10	TSL:1	c.450+3055G>C		intron	N/A	ENSP00000343060.6	Q6R954

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250794 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457002 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725196

African (AFR) AF: 0.00 AC: 0 AN: 33318

American (AMR) AF: 0.0000224 AC: 1 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107862

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.00079	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.92
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.057
Sift	Benign	0.098	T
Sift4G	Benign	0.18	T
Polyphen		0.25	B
Vest4		0.41
MutPred		0.42		Loss of helix (P = 0.0041)
MVP		0.23
MPC		0.11
ClinPred		0.19	T
GERP RS		2.8
Varity_R		0.038
gMVP		0.27
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs755947684; hg19: chr22-42995721;