Genetic Variant NM_015584.5:c.107C>T (chr17-28357342-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015584.5(POLDIP2):c.107C>T(p.Ala36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,574,966 control chromosomes in the GnomAD database, including 613 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 31 hom., cov: 33)

Exomes 𝑓: 0.026 ( 582 hom. )

Consequence

POLDIP2
NM_015584.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.518

Variant links:

Genes affected

POLDIP2 (HGNC:23781): (DNA polymerase delta interacting protein 2) This gene encodes a protein that interacts with the DNA polymerase delta p50 subunit, as well as with proliferating cell nuclear antigen. The encoded protein maybe play a role in the ability of the replication fork to bypass DNA lesions. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

POLDIP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025236309).

BP6

Variant 17-28357342-G-A is Benign according to our data. Variant chr17-28357342-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1205722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0166 (2528/152354) while in subpopulation NFE AF= 0.027 (1838/68024). AF 95% confidence interval is 0.026. There are 31 homozygotes in gnomad4. There are 1134 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLDIP2	NM_015584.5 link	c.107C>T	p.Ala36Val	missense_variant	Exon 1 of 11	ENST00000540200.6	NP_056399.1	Q9Y2S7
POLDIP2	NM_001290145.2 link	c.107C>T	p.Ala36Val	missense_variant	Exon 1 of 11		NP_001277074.1	Q9Y2S7B4DEM9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLDIP2	ENST00000540200.6 link	c.107C>T	p.Ala36Val	missense_variant	Exon 1 of 11	1	NM_015584.5	ENSP00000475924.2		Q9Y2S7
POLDIP2	ENST00000618887.2 link	c.107C>T	p.Ala36Val	missense_variant	Exon 1 of 11	2		ENSP00000477665.2		B4DEM9

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2528

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00461

Gnomad AMI

AF:

0.0484

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00351

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0270

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.0215

AC:

3218

AN:

149492

Hom.:

AF XY:

0.0216

AC XY:

1864

AN XY:

86396

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.000117

Gnomad SAS exome

AF:

0.00625

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0346

Gnomad OTH exome

AF:

0.0266

GnomAD4 exome

AF:

0.0258

AC:

36651

AN:

1422612

Hom.:

582

Cov.:

AF XY:

0.0253

AC XY:

17875

AN XY:

707464

show subpopulations

Gnomad4 AFR exome

AF:

0.00412

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0165

Gnomad4 EAS exome

AF:

0.0000270

Gnomad4 SAS exome

AF:

0.00543

Gnomad4 FIN exome

AF:

0.0140

Gnomad4 NFE exome

AF:

0.0301

Gnomad4 OTH exome

AF:

0.0218

GnomAD4 genome

AF:

0.0166

AC:

2528

AN:

152354

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1134

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00459

Gnomad4 AMR

AF:

0.0128

Gnomad4 ASJ

AF:

0.0173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0120

Gnomad4 NFE

AF:

0.0270

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0218

Hom.:

Bravo

AF:

0.0172

TwinsUK

AF:

0.0332

AC:

123

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00350

AC:

ESP6500EA

AF:

0.0215

AC:

152

ExAC

AF:

0.0164

AC:

1810

Asia WGS

AF:

0.00202

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 09, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.014

T;.

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0025

T;T

MutationAssessor

Benign

0.69

N;.

PrimateAI

Uncertain

0.70

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.23

MPC

0.52

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.023

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over