19-50407357-G-C

Variant names:

• chr19-50407357-G-C
• NM_002691.4:c.1717G>C

Variant summary

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

The NM_002691.4(POLD1):​c.1717G>C​(p.Val573Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.83

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]

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=0.17290711).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1717G>C	p.Val573Leu	missense_variant	Exon 14 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.1717G>C	p.Val573Leu	missense_variant	Exon 14 of 27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152018 Hom.: 0 Cov.: 30

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

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: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.21
DEOGEN2	Benign	0.090	T;.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.59	N;.;.;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.70	N;.;.;.
REVEL	Benign	0.23
Sift	Benign	1.0	T;.;.;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0030	B;.;.;B
Vest4		0.25
MutPred		0.32		Loss of methylation at K574 (P = 0.0518);Loss of methylation at K574 (P = 0.0518);Loss of methylation at K574 (P = 0.0518);Loss of methylation at K574 (P = 0.0518);
MVP		0.48
MPC		0.99
ClinPred		0.64	D
GERP RS		4.1
Varity_R		0.17
gMVP		0.31

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: chr19-50910614;