rs9328764

Positions:

• chr4-2174727-G-A

Variant summary

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

The NM_181808.4(POLN):​c.1273C>T​(p.Arg425Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,606,238 control chromosomes in the GnomAD database, including 24,550 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.25 (7143 hom., cov: 32)
  • Exomes 𝑓: 0.13 (17407 hom.)
• Consequence: POLN NM_181808.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52

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=6.107092E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLN	NM_181808.4	c.1273C>T	p.Arg425Cys	missense_variant	10/26	ENST00000511885.6	NP_861524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLN	ENST00000511885.6	c.1273C>T	p.Arg425Cys	missense_variant	10/26	5	NM_181808.4	ENSP00000435506.1
ENSG00000290263	ENST00000672725.1	n.2636C>T		non_coding_transcript_exon_variant	10/19			ENSP00000500518.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37428 AN: 151788 Hom.: 7125 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.0846

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.250

GnomAD3 exomes AF: 0.185 AC: 46432 AN: 250554 Hom.: 6200 AF XY: 0.173 AC XY: 23458 AN XY: 135500

Gnomad AFR exome AF: 0.519

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.392

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.0940

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.129 AC: 186981 AN: 1454332 Hom.: 17407 Cov.: 31 AF XY: 0.128 AC XY: 92657 AN XY: 723868

Gnomad4 AFR exome AF: 0.531

Gnomad4 AMR exome AF: 0.254

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.0927

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.247 AC: 37498 AN: 151906 Hom.: 7143 Cov.: 32 AF XY: 0.245 AC XY: 18190 AN XY: 74240

Gnomad4 AFR AF: 0.515

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.0846

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.252

Alfa AF: 0.147 Hom.: 5788

Bravo AF: 0.273

TwinsUK AF: 0.0992 AC: 368

ALSPAC AF: 0.105 AC: 406

ESP6500AA AF: 0.504 AC: 2220

ESP6500EA AF: 0.116 AC: 995

ExAC AF: 0.190 AC: 23013

Asia WGS AF: 0.329 AC: 1145 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0025	T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.25	T;.
MetaRNN	Benign	0.00061	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.4	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	2.2	N;N
REVEL	Benign	0.13
Sift	Benign	0.26	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0	B;B
Vest4		0.055
MPC		0.098
ClinPred		0.015	T
GERP RS		4.5
Varity_R		0.19
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs9328764; hg19: chr4-2176454; COSMIC: COSV67026825;