rs547831370

chr19-50407385-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002691.4(POLD1):c.1745C>T(p.Thr582Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,610,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T582A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.15

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4126715).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.1745C>T	p.Thr582Met	missense_variant	14/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.1745C>T	p.Thr582Met	missense_variant	14/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152000 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000244 AC: 6 AN: 245544 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000330

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1458390 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 725176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152000 Hom.: 0 Cov.: 30 AF XY: 0.0000539 AC XY: 4 AN XY: 74232

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2017

This variant is denoted POLD1 c.1745C>T at the cDNA level, p.Thr582Met (T582M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been reported a pediatric patient with B-lineage acute lymphoblastic leukemia (Zhang 2015). POLD1 Thr582Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLD1 Thr582Met is located in the polymerase domain (Preston 2010). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether POLD1 Thr582Met is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 582 of the POLD1 protein (p.Thr582Met). This variant is present in population databases (rs547831370, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 408117). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.2	N;.;.;.
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.65	P;.;.;P
Vest4		0.49
MVP		0.62
MPC		1.6
ClinPred		0.38	T
GERP RS		4.1
Varity_R		0.64
gMVP		0.38

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: rs547831370; hg19: chr19-50910642; COSMIC: COSV70955118; COSMIC: COSV70955118;