rs369732588

Positions:

• chr12-132661167-GAAA-G
• chr12-132661167-GAAA-GA
• chr12-132661167-GAAA-GAA
• chr12-132661167-GAAA-GAAAA
• chr12-132661167-GAAA-GAAAAA
• chr12-132661167-GAAA-GAAAAAAA
• chr12-132661167-GAAA-GAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_006231.4(POLE):​c.2865-6_2865-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,373,858 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000074 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.200

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 12-132661167-GAAA-G is Benign according to our data. Variant chr12-132661167-GAAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 439267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132661167-GAAA-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000256 (317/1239568) while in subpopulation AMR AF= 0.000872 (27/30978). AF 95% confidence interval is 0.000615. There are 0 homozygotes in gnomad4_exome. There are 190 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.2865-6_2865-4delTTT		splice_region_variant, intron_variant		ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.2865-6_2865-4delTTT		splice_region_variant, intron_variant		1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.00000745 AC: 1 AN: 134290 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000256 AC: 317 AN: 1239568 Hom.: 0 AF XY: 0.000309 AC XY: 190 AN XY: 615052

Gnomad4 AFR exome AF: 0.000184

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.000615

Gnomad4 EAS exome AF: 0.000221

Gnomad4 SAS exome AF: 0.000653

Gnomad4 FIN exome AF: 0.000461

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.000368

GnomAD4 genome AF: 0.00000745 AC: 1 AN: 134290 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 64608

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000162

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The POLE c.2865-6_2865-4delTTT variant was not identified in the literature nor was it identified in the Cosmic, or MutDB databases. The variant was also identified in dbSNP (ID: rs778801383) as NA, and in ClinVar (1x as a variant of uncertain significance). 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). The c.2865-6_2865-4delTTT variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. More over the intronic sequence form position 2865-17 to 2865-4 is a repetitive run of thymine making it unlikely that this particular sequence change would affect splicing. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although the available information suggests a benign role. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 29, 2019	- -

Hereditary cancer-predisposing syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

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: rs369732588; hg19: chr12-133237753;