4-2072230-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181808.4(POLN):c.2587G>A(p.Gly863Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,451,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: POLN NM_181808.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.348

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06864157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLN	NM_181808.4	c.2587G>A	p.Gly863Ser	missense_variant	26/26	ENST00000511885.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLN	ENST00000511885.6	c.2587G>A	p.Gly863Ser	missense_variant	26/26	5	NM_181808.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 243736 Hom.: 0 AF XY: 0.00000753 AC XY: 1 AN XY: 132738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000660

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000912

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1451182 Hom.: 0 Cov.: 34 AF XY: 0.00000555 AC XY: 4 AN XY: 720776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2023

The c.2587G>A (p.G863S) alteration is located in exon 24 (coding exon 24) of the POLN gene. This alteration results from a G to A substitution at nucleotide position 2587, causing the glycine (G) at amino acid position 863 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.40
Dann	Benign	0.95
DEOGEN2	Benign	0.0035	T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.38	T;.
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.99	N;N
REVEL	Benign	0.045
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.037	D;D
Polyphen		0.67	P;P
Vest4		0.14
MutPred		0.20		Loss of glycosylation at P865 (P = 0.0094);Loss of glycosylation at P865 (P = 0.0094);
MVP		0.13
MPC		0.074
ClinPred		0.046	T
GERP RS		1.4
Varity_R		0.076
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs745732430; hg19: chr4-2073957;