Genetic Variant NM_181808.4:c.1006G>A (chr4-2193219-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_181808.4(POLN):c.1006G>A(p.Gly336Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,588,602 control chromosomes in the GnomAD database, including 24,911 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.25 ( 7750 hom., cov: 31)

Exomes 𝑓: 0.12 ( 17161 hom. )

Consequence

POLN
NM_181808.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.108

Publications

25 publications found

Variant links:

Genes affected

POLN (HGNC:18870): (DNA polymerase nu) This gene encodes a DNA polymerase type-A family member. The encoded protein plays a role in DNA repair and homologous recombination. This gene shares its 5' exons with some transcripts from overlapping GeneID: 79441, which encodes an augmentin-like protein complex subunit. [provided by RefSeq, Dec 2014]

POLN links:

ENSG00000290263 (HGNC:):

ENSG00000290263 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.4366716E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLN	NM_181808.4 link	c.1006G>A	p.Gly336Ser	missense_variant	Exon 7 of 26	ENST00000511885.6	NP_861524.2	Q7Z5Q5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLN	ENST00000511885.6 link	c.1006G>A	p.Gly336Ser	missense_variant	Exon 7 of 26	5	NM_181808.4	ENSP00000435506.1		Q7Z5Q5-1
ENSG00000290263	ENST00000672725.1 link	n.2596G>A		non_coding_transcript_exon_variant	Exon 9 of 19			ENSP00000500518.1		A0A5F9ZHQ7

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38541

AN:

151710

Hom.:

7733

Cov.:

show subpopulations

Gnomad AFR

AF:

0.543

Gnomad AMI

AF:

0.225

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.378

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.0836

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.255

GnomAD2 exomes

AF:

0.184

AC:

45419

AN:

246406

AF XY:

0.172

show subpopulations

Gnomad AFR exome

AF:

0.548

Gnomad AMR exome

AF:

0.247

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.386

Gnomad FIN exome

AF:

0.0934

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.177

GnomAD4 exome

AF:

0.125

AC:

179482

AN:

1436776

Hom.:

17161

Cov.:

AF XY:

0.125

AC XY:

89252

AN XY:

715790

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.558

AC:

17599

AN:

31532

American (AMR)

AF:

0.250

AC:

10869

AN:

43410

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

3654

AN:

25844

East Asian (EAS)

AF:

0.352

AC:

13785

AN:

39108

South Asian (SAS)

AF:

0.151

AC:

12783

AN:

84498

European-Finnish (FIN)

AF:

0.0921

AC:

4906

AN:

53290

Middle Eastern (MID)

AF:

0.224

AC:

1274

AN:

5688

European-Non Finnish (NFE)

AF:

0.0958

AC:

104834

AN:

1094116

Other (OTH)

AF:

0.165

AC:

9778

AN:

59290

⚠️ 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: 0.391

Heterozygous variant carriers

6161

12321

18482

24642

30803

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4048

8096

12144

16192

20240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.254

AC:

38610

AN:

151826

Hom.:

7750

Cov.:

AF XY:

0.252

AC XY:

18670

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.543

AC:

22417

AN:

41246

American (AMR)

AF:

0.245

AC:

3738

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

551

AN:

3464

East Asian (EAS)

AF:

0.377

AC:

1949

AN:

5168

South Asian (SAS)

AF:

0.173

AC:

835

AN:

4820

European-Finnish (FIN)

AF:

0.0836

AC:

884

AN:

10576

Middle Eastern (MID)

AF:

0.236

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.109

AC:

7422

AN:

67986

Other (OTH)

AF:

0.257

AC:

541

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1154

2308

3461

4615

5769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.169

Hom.:

11598

Bravo

AF:

0.284

TwinsUK

AF:

0.0990

AC:

367

ALSPAC

AF:

0.105

AC:

404

ESP6500AA

AF:

0.535

AC:

2357

ESP6500EA

AF:

0.115

AC:

992

ExAC

AF:

0.191

AC:

23221

Asia WGS

AF:

0.330

AC:

1150

AN:

3478

EpiCase

AF:

0.121

EpiControl

AF:

0.126

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

6.7

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.00081

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.67

T;.

MetaRNN

Benign

0.000054

T;T

MetaSVM

Benign

-0.97

PhyloP100

-0.11

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.71

N;N

REVEL

Benign

0.077

Sift

Benign

0.21

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.0060

B;B

Vest4

0.042

MPC

0.076

ClinPred

0.000063

GERP RS

0.38

Varity_R

0.23

gMVP

0.45

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over