chr19-50416437-G-C

Position:

• chr19-50416437-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002691.4(POLD1):​c.2862G>C​(p.Thr954Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,549,980 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (22 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.99

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-50416437-G-C is Benign according to our data. Variant chr19-50416437-G-C is described in ClinVar as [Benign]. Clinvar id is 221052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50416437-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1544/152304) while in subpopulation AFR AF= 0.0347 (1442/41556). AF 95% confidence interval is 0.0332. There are 20 homozygotes in gnomad4. There are 721 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1544 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2862G>C	p.Thr954Thr	synonymous_variant	23/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2862G>C	p.Thr954Thr	synonymous_variant	23/27	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.69G>C	p.Thr23Thr	synonymous_variant	2/10	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1538 AN: 152186 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00244 AC: 379 AN: 155462 Hom.: 2 AF XY: 0.00164 AC XY: 135 AN XY: 82406

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000437

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000831

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.00102 AC: 1428 AN: 1397676 Hom.: 22 Cov.: 31 AF XY: 0.000856 AC XY: 590 AN XY: 689560

Gnomad4 AFR exome AF: 0.0370

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.0101 AC: 1544 AN: 152304 Hom.: 20 Cov.: 32 AF XY: 0.00968 AC XY: 721 AN XY: 74478

Gnomad4 AFR AF: 0.0347

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.0123

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2018	Variant summary: POLD1 c.2862G>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0036 in 179660 control chromosomes, predominantly within the African subpopulation at a frequency of 0.036 in the gnomAD database, including 8 homozygotes. The observed variant frequency within African control individuals is approximately 2534 fold above the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Although POLD1 pseudogenes may complicate NGS mapping, our analysis shows that the variant of interest lies within a region that is not homologous to any other region of the genome, suggesting the variant is real and localized to the POLD1 gene. To our knowledge, no occurrence of c.2862G>C in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Colorectal cancer, susceptibility to, 10 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 10, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLD1 p.Thr954Thr variant was not identified in the literature nor was it identified in the Cosmic and MutDB databases. The variant was identified in dbSNP (ID: rs3219440) “With Likely benign allele”,bClinVar (classified benign by Invitae, Counsyl, Ambry Genetics, Quest Diagnostics Nichols Institute San Juan Capistrano; and likely benign GeneDx), Clinvitae (2x), and in control databases in 651 (8 homozygous) of 179660 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 587 (8 homozygous) of 16318 chromosomes (freq: 0.04), Other in 5 of 4808 chromosomes (freq: 0.001), Latino in 52 of 24830 chromosomes (freq: 0.002), European Non-Finnish in 6 of 71940 chromosomes (freq: 0.00008), and South Asian in 1 of 22912 chromosomes (freq: 0.00004), while not observed in the Ashkenazi Jewish, East Asian and European Finnish populations. The p.Thr954= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2015

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.46
DANN	Benign	0.83

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: rs3219440; hg19: chr19-50919694; COSMIC: COSV99068280; COSMIC: COSV99068280;