rs1555789811

Positions:

• chr19-50401918-C-A
• chr19-50401918-C-G
• chr19-50401918-C-T

Variant summary

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

The NM_002691.4(POLD1):​c.457C>A​(p.Pro153Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.457C>A	p.Pro153Thr	missense_variant	4/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.457C>A	p.Pro153Thr	missense_variant	4/27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461750 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.;D
Eigen	Benign	0.13
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.72	.;.;T;D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.4	M;.;.;.;M
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.7	D;.;.;.;.
REVEL	Benign	0.080
Sift	Uncertain	0.0010	D;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.92	P;.;.;.;P
Vest4		0.44
MutPred		0.68		Gain of phosphorylation at P153 (P = 0.0219);Gain of phosphorylation at P153 (P = 0.0219);Gain of phosphorylation at P153 (P = 0.0219);Gain of phosphorylation at P153 (P = 0.0219);Gain of phosphorylation at P153 (P = 0.0219);
MVP		0.67
MPC		0.38
ClinPred		0.93	D
GERP RS		3.0
Varity_R		0.72
gMVP		0.67

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: rs1555789811; hg19: chr19-50905175;