19-50406330-C-T

Variant names:

• chr19-50406330-C-T
• rs374719944
• NM_002691.4:c.1383+8C>T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002691.4(POLD1):​c.1383+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,613,478 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: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: POLD1 NM_002691.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003801
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: -0.690

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-50406330-C-T is Benign according to our data. Variant chr19-50406330-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1383+8C>T		splice_region_variant, intron_variant	Intron 11 of 26	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.1383+8C>T		splice_region_variant, intron_variant	Intron 11 of 26	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000112 AC: 28 AN: 250514 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000687

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1461292 Hom.: 1 Cov.: 36 AF XY: 0.000122 AC XY: 89 AN XY: 726898

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000891

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74404

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.0000529

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Benign:5

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2016

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polymerase proofreading-related adenomatous polyposis Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLD1 c.1383+8C>T variant was not identified in the literature. The variant was identified in dbSNP (ID: rs374719944) as "With Likely benign allele", in ClinVar (classified as likely benign by Invitae, Counsyl, GeneDx, and Quest Diagnostics). The variant was identified in control databases in 31 of 276268 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6446 chromosomes (freq: 0.0002), Latino in 1 of 34382 chromosomes (freq: 0.00003), European Non-Finnish in 7 of 126178 chromosomes (freq: 0.000055), East Asian in 2 of 18856 chromosomes (freq: 0.0001), and South Asian in 20 of 30752 chromosomes (freq: 0.00065), while the variant was not observed in the African, Ashkenazi Jewish, or Finnish populations. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Benign:1

Jun 09, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Oct 28, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Nov 20, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.84
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.014
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: rs374719944; hg19: chr19-50909587;