rs796285537

Positions:

• chr19-50401932-GC-TT

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_002691.4(POLD1):​c.463+8_463+9delinsTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLD1 NM_002691.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.220

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 -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-50401932-GC-TT is Benign according to our data. Variant chr19-50401932-GC-TT is described in ClinVar as [Likely_benign]. Clinvar id is 221053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.463+8_463+9delinsTT		splice_region_variant, intron_variant		ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.463+8_463+9delinsTT		splice_region_variant, intron_variant		1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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	Jul 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2016

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. -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLD1 c.463+8_463+9delinsTT variant was not identified in the literature nor was it identified in MutDB. The variant was identified in dbSNP (ID: rs796285537 as With other allele) and ClinVar (3x as likely benign and 1x as benign). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). However, each nucleotide substitution included in this variant was identified in control databases: c.463+8G>T at a frequency of 0.1, c.463+9C>T at a frequency of 0.007, and both occurring at the highest frequency in the African population (Genome Aggregation Database Feb 27, 2017). In addition, the two variants are sometimes identified in both ExAC and Gnomad as occurring in cis (c.463+8_463+9delinsTT variant), which can be seen in the IGV tracks provided; however, frequency information is not available at this time. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although available information suggests a benign role. This variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 26, 2016

Variant summary: The POLD1 c.463+8_463+9delinsTT variant involves the alteration of non-conserved nucleotides, resulting in a intronic change. This delins variant is not found in ExAC; however, the individual variants that form the variant of interest, viz. 19:50905189 G / T and 19:50905190 C / T are found at allele frequencies of 0.1145 (13864/ 121128) and 0.007434 (901/121202), respectively. In African sub-population, they have allele frequencies of 0.2939 and 0.08015, respectively. Therefore, it is highly likely they are in a considerable linkage disequilibrium such that the variant of interest also has a frequency that exceeds the estimated maximal expected allele frequency (0.00142) based on the disease prevalence of CRC. One clinical lab in ClinVar has classified it bas benign. The variant of interest has not been reported in affected individuals via publications, to our knowledge. Taken together, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

True Health Diagnostics

Oct 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796285537; hg19: chr19-50905189;