chr4-2174727-G-A

Variant names:

• chr4-2174727-G-A
• rs9328764
• NM_181808.4:c.1273C>T

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 the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R425H) has been classified as Uncertain significance.

• 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 rank	MANE	Protein	UniProt
POLN	NM_181808.4	c.1273C>T	p.Arg425Cys	missense_variant	Exon 10 of 26	ENST00000511885.6	NP_861524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLN	ENST00000511885.6	c.1273C>T	p.Arg425Cys	missense_variant	Exon 10 of 26	5	NM_181808.4	ENSP00000435506.1
ENSG00000290263	ENST00000672725.1	n.2636C>T		non_coding_transcript_exon_variant	Exon 10 of 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;