19-50415719-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_002691.4(POLD1):c.2718-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,535,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: POLD1 NM_002691.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001161
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.540

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-50415719-C-T is Benign according to our data. Variant chr19-50415719-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50415719-C-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.2718-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.2718-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000662 AC: 10 AN: 150986 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000393

Gnomad SAS AF: 0.000838

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.000290 AC: 43 AN: 148468 Hom.: 0 AF XY: 0.000325 AC XY: 26 AN XY: 80074

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000751

Gnomad SAS exome AF: 0.000870

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 241 AN: 1384054 Hom.: 1 Cov.: 33 AF XY: 0.000197 AC XY: 135 AN XY: 683728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000139

Gnomad4 ASJ exome AF: 0.0000400

Gnomad4 EAS exome AF: 0.000548

Gnomad4 SAS exome AF: 0.000934

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.0000662 AC: 10 AN: 151106 Hom.: 0 Cov.: 29 AF XY: 0.0000542 AC XY: 4 AN XY: 73798

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000394

Gnomad4 SAS AF: 0.000839

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.000477

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000529

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 07, 2024	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

POLD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	14
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.056
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: rs368965066; hg19: chr19-50918976;