19-50414944-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002691.4(POLD1):​c.2518G>T​(p.Val840Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

6
8
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.28
Variant links:
Genes affected
POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLD1NM_002691.4 linkc.2518G>T p.Val840Leu missense_variant Exon 20 of 27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.2518G>T p.Val840Leu missense_variant Exon 20 of 27 1 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.87e-7
AC:
1
AN:
1455268
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
723566
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:
0.0000190
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Benign
-0.023
T
BayesDel_noAF
Benign
-0.27
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Benign
0.36
T;.;.;T
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Pathogenic
0.99
.;.;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.90
D;D;D;D
MetaSVM
Benign
-0.66
T
MutationAssessor
Pathogenic
3.3
M;.;.;M
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-2.9
D;.;.;.
REVEL
Uncertain
0.38
Sift
Uncertain
0.0010
D;.;.;.
Sift4G
Uncertain
0.0020
D;D;D;D
Polyphen
0.98
D;.;.;D
Vest4
0.55
MutPred
0.80
Loss of catalytic residue at V840 (P = 0.0368);.;.;Loss of catalytic residue at V840 (P = 0.0368);
MVP
0.73
MPC
1.6
ClinPred
0.99
D
GERP RS
3.5
Varity_R
0.68
gMVP
0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50918201; API