rs142483063

Variant names:

• chr4-2085646-C-T
• rs142483063
• NM_181808.4:c.2164G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_181808.4(POLN):​c.2164G>A​(p.Ala722Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: POLN NM_181808.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.186
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048138767).

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.2164G>A	p.Ala722Thr	missense	Exon 21 of 26	NP_861524.2	Q7Z5Q5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLN	ENST00000511885.6	TSL:5 MANE Select	c.2164G>A	p.Ala722Thr	missense	Exon 21 of 26	ENSP00000435506.1	Q7Z5Q5-1
	POLN	ENST00000382865.5	TSL:1	c.2164G>A	p.Ala722Thr	missense	Exon 19 of 24	ENSP00000372316.1	Q7Z5Q5-1
	POLN	ENST00000511098.1	TSL:1	c.1060G>A	p.Ala354Thr	missense	Exon 14 of 19	ENSP00000426401.1	H0YA88

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251450 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727184

African (AFR) AF: 0.000149 AC: 5 AN: 33474

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74368

African (AFR) AF: 0.000362 AC: 15 AN: 41444

American (AMR) AF: 0.000262 AC: 4 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000860 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.86
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.19
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.050
Sift	Benign	0.48	T
Sift4G	Benign	0.96	T
Polyphen		0.025	B
Vest4		0.19
MVP		0.22
MPC		0.075
ClinPred		0.031	T
GERP RS		1.6
Varity_R		0.096
gMVP		0.36
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs142483063; hg19: chr4-2087373;