rs10011549

Positions:

• chr4-2193219-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 13/19 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.25 (7750 hom., cov: 31)
  • Exomes 𝑓: 0.12 (17161 hom.)
• Consequence: POLN NM_181808.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.108

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]

ENSG00000290263 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
POLN	NM_181808.4	c.1006G>A	p.Gly336Ser	missense_variant	7/26	ENST00000511885.6	NP_861524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLN	ENST00000511885.6	c.1006G>A	p.Gly336Ser	missense_variant	7/26	5	NM_181808.4	ENSP00000435506.1
ENSG00000290263	ENST00000672725.1	n.2596G>A		non_coding_transcript_exon_variant	9/19			ENSP00000500518.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38541 AN: 151710 Hom.: 7733 Cov.: 31

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

GnomAD3 exomes AF: 0.184 AC: 45419 AN: 246406 Hom.: 6180 AF XY: 0.172 AC XY: 22925 AN XY: 133308

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 SAS exome AF: 0.149

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.: 30 AF XY: 0.125 AC XY: 89252 AN XY: 715790

Gnomad4 AFR exome AF: 0.558

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.352

Gnomad4 SAS exome AF: 0.151

Gnomad4 FIN exome AF: 0.0921

Gnomad4 NFE exome AF: 0.0958

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.254 AC: 38610 AN: 151826 Hom.: 7750 Cov.: 31 AF XY: 0.252 AC XY: 18670 AN XY: 74204

Gnomad4 AFR AF: 0.543

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.0836

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.257

Alfa AF: 0.149 Hom.: 6121

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	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.7
DANN	Benign	0.68
DEOGEN2	Benign	0.00081	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.67	T;.
MetaRNN	Benign	0.000054	T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.29	T
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	T
GERP RS		0.38
Varity_R		0.23
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs10011549; hg19: chr4-2194946;