Variant 4-2128131-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_181808.4(POLN):c.1964C>T(p.Ser655Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

POLN
NM_181808.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.48

Variant links:

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]

POLN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLN	NM_181808.4 linkuse as main transcript	c.1964C>T	p.Ser655Phe	missense_variant	19/26	ENST00000511885.6	NP_861524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLN	ENST00000511885.6 linkuse as main transcript	c.1964C>T	p.Ser655Phe	missense_variant	19/26	5	NM_181808.4	ENSP00000435506	P1	Q7Z5Q5-1
POLN	ENST00000382865.5 linkuse as main transcript	c.1964C>T	p.Ser655Phe	missense_variant	17/24	1		ENSP00000372316	P1	Q7Z5Q5-1
POLN	ENST00000511098.1 linkuse as main transcript	c.863C>T	p.Ser288Phe	missense_variant	12/19	1		ENSP00000426401
POLN	ENST00000514858.5 linkuse as main transcript	n.971C>T		non_coding_transcript_exon_variant	10/14	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450362

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722342

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.1964C>T (p.S655F) alteration is located in exon 17 (coding exon 17) of the POLN gene. This alteration results from a C to T substitution at nucleotide position 1964, causing the serine (S) at amino acid position 655 to be replaced by a phenylalanine (F). 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

0.15

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.88

D;.

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

0.55

N;N

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.5

D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

0.93

P;P

Vest4

0.57

MutPred

0.68

Loss of disorder (P = 0.011);Loss of disorder (P = 0.011);

MVP

0.96

MPC

0.39

ClinPred

0.95

GERP RS

4.3

Varity_R

0.88

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.25

Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over