4-2072974-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181808.4(POLN):​c.2511G>T​(p.Gln837His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

POLN
NM_181808.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.574
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.18216643).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLNNM_181808.4 linkc.2511G>T p.Gln837His missense_variant Exon 25 of 26 ENST00000511885.6 NP_861524.2 Q7Z5Q5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLNENST00000511885.6 linkc.2511G>T p.Gln837His missense_variant Exon 25 of 26 5 NM_181808.4 ENSP00000435506.1 Q7Z5Q5-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152152
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000282
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250940
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135688
show subpopulations
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:
0.00
Gnomad FIN exome
AF:
0.0000467
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461050
Hom.:
0
Cov.:
31
AF XY:
0.0000206
AC XY:
15
AN XY:
726872
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000758
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152152
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000282
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000283
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2511G>T (p.Q837H) alteration is located in exon 23 (coding exon 23) of the POLN gene. This alteration results from a G to T substitution at nucleotide position 2511, causing the glutamine (Q) at amino acid position 837 to be replaced by a histidine (H). 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
0.10
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
11
DANN
Uncertain
0.99
DEOGEN2
Benign
0.28
T;T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.63
T;.
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.18
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.81
L;L
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.6
N;N
REVEL
Benign
0.037
Sift
Benign
0.061
T;T
Sift4G
Benign
0.38
T;T
Polyphen
0.082
B;B
Vest4
0.34
MutPred
0.48
Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP
0.24
MPC
0.074
ClinPred
0.084
T
GERP RS
2.2
Varity_R
0.33
gMVP
0.26

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs746339339; hg19: chr4-2074701; API