12-132661167-G-GAA

Position:

• chr12-132661167-G-GAA

Variant summary

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

The NM_006231.4(POLE):​c.2865-5_2865-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,368,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00098 (0 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.191

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-G-GAA is Benign according to our data. Variant chr12-132661167-G-GAA is described in ClinVar as [Likely_benign]. Clinvar id is 801260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000985 (1215/1233756) while in subpopulation SAS AF= 0.0027 (185/68468). AF 95% confidence interval is 0.00238. There are 0 homozygotes in gnomad4_exome. There are 638 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.2865-5_2865-4dupTT		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.2865-5_2865-4dupTT		splice_region_variant, intron_variant		1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.000156 AC: 21 AN: 134284 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000249

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: 0.000129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000178

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000985 AC: 1215 AN: 1233756 Hom.: 0 Cov.: 0 AF XY: 0.00104 AC XY: 638 AN XY: 612260

Gnomad4 AFR exome AF: 0.00159

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.00270

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.000783

Gnomad4 OTH exome AF: 0.00115

GnomAD4 genome AF: 0.000156 AC: 21 AN: 134284 Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 9 AN XY: 64610

Gnomad4 AFR AF: 0.000249

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000129

Gnomad4 NFE AF: 0.000178

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 11, 2019

- -

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: rs369732588; hg19: chr12-133237753;