rs1060501801

Positions:

• chr19-50417259-A-T

Variant summary

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

The NM_002691.4(POLD1):​c.3208A>T​(p.Ile1070Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97

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]

ENSG00000142539 (HGNC:):

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.3208A>T	p.Ile1070Phe	missense_variant	26/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.3208A>T	p.Ile1070Phe	missense_variant	26/27	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.415A>T	p.Ile139Phe	missense_variant	5/10	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443668 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 717574

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 02, 2016

This sequence change replaces isoleucine with phenylalanine at codon 1070 of the POLD1 protein (p.Ile1070Phe). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a POLD1-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T;.;.;T
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.62	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.0	M;.;.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.9	D;.;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D;.;.;.
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.92	P;.;.;P
Vest4		0.51
MutPred		0.38		Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);
MVP		0.65
MPC		1.5
ClinPred		0.97	D
GERP RS		1.9
Varity_R		0.72
gMVP		0.42

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

Other links and lift over

dbSNP: rs1060501801; hg19: chr19-50920516;