12-132661167-GAAAAA-GAA

Variant names:

• chr12-132661167-GAAA-G
• rs369732588
• NM_006231.4:c.2865-6_2865-4delTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

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
• Publications: 4 publications found

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]

POLE Gene-Disease associations (from GenCC):

• POLE-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

  Inheritance: AR Classification: STRONG Submitted by: G2P
• IMAGe syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant 12-132661167-GAAA-G is Benign according to our data. Variant chr12-132661167-GAAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 439267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006231.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.2865-6_2865-4delTTT		splice_region intron	N/A	NP_006222.2	Q07864

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	ENST00000320574.10	TSL:1 MANE Select	c.2865-6_2865-4delTTT		splice_region intron	N/A	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.2784-6_2784-4delTTT		splice_region intron	N/A	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*1912-6_*1912-4delTTT		splice_region intron	N/A	ENSP00000442578.1	F5H7E4

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

GnomAD2 exomes AF: 0.00109 AC: 117 AN: 106982 AF XY: 0.00105

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.000493

Gnomad FIN exome AF: 0.00303

Gnomad NFE exome AF: 0.000863

Gnomad OTH exome AF: 0.00155

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000184 AC: 5 AN: 27164

American (AMR) AF: 0.000872 AC: 27 AN: 30978

Ashkenazi Jewish (ASJ) AF: 0.000615 AC: 13 AN: 21136

East Asian (EAS) AF: 0.000221 AC: 8 AN: 36230

South Asian (SAS) AF: 0.000653 AC: 45 AN: 68932

European-Finnish (FIN) AF: 0.000461 AC: 19 AN: 41214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4588

European-Non Finnish (NFE) AF: 0.000189 AC: 181 AN: 957716

Other (OTH) AF: 0.000368 AC: 19 AN: 51610

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00 AC: 0 AN: 36126

American (AMR) AF: 0.00 AC: 0 AN: 13540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3228

East Asian (EAS) AF: 0.00 AC: 0 AN: 4652

South Asian (SAS) AF: 0.00 AC: 0 AN: 4176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000162 AC: 1 AN: 61908

Other (OTH) AF: 0.00 AC: 0 AN: 1768

Alfa AF: 0.00 Hom.: 5

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs369732588; hg19: chr12-133237753;