rs10011549

Variant names:

• chr4-2193219-C-T
• rs10011549
• NM_181808.4:c.1006G>A

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.108
• Publications: 25 publications found

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181808.4. 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
	POLN	NM_181808.4	MANE Select	c.1006G>A	p.Gly336Ser	missense	Exon 7 of 26	NP_861524.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLN	ENST00000511885.6	TSL:5 MANE Select	c.1006G>A	p.Gly336Ser	missense	Exon 7 of 26	ENSP00000435506.1
	POLN	ENST00000382865.5	TSL:1	c.1006G>A	p.Gly336Ser	missense	Exon 5 of 24	ENSP00000372316.1
	ENSG00000290263	ENST00000672725.1		n.2596G>A		non_coding_transcript_exon	Exon 9 of 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

GnomAD2 exomes AF: 0.184 AC: 45419 AN: 246406 AF XY: 0.172

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

⚠️ 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.

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

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: 69 AN: 292

European-Non Finnish (NFE) AF: 0.109 AC: 7422 AN: 67986

Other (OTH) AF: 0.257 AC: 541 AN: 2108

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 v4.9

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
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
MetaSVM	Benign	-0.97	T
PhyloP100		-0.11
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.077
Sift	Benign	0.21	T
Sift4G	Benign	0.86	T
Polyphen		0.0060	B
Vest4		0.042
MPC		0.076
ClinPred		0.000063	T
GERP RS		0.38
Varity_R		0.23
gMVP		0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10011549; hg19: chr4-2194946; COSMIC: COSV107494088;