12-132665463-T-C

Variant names:

• chr12-132665463-T-C
• rs75329753
• NM_006231.4:c.2320-13A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006231.4(POLE):​c.2320-13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,601,642 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (65 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (78 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.00
• Publications: 2 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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 -16 ACMG points.

• BP6: Variant 12-132665463-T-C is Benign according to our data. Variant chr12-132665463-T-C is described in ClinVar as Benign. ClinVar VariationId is 380230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.2320-13A>G		intron	N/A	NP_006222.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	ENST00000320574.10	TSL:1 MANE Select	c.2320-13A>G		intron	N/A	ENSP00000322570.5
	POLE	ENST00000535270.5	TSL:1	c.2239-13A>G		intron	N/A	ENSP00000445753.1
	POLE	ENST00000537064.5	TSL:1	n.*1367-13A>G		intron	N/A	ENSP00000442578.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2592 AN: 152160 Hom.: 65 Cov.: 31

Gnomad AFR AF: 0.0574

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00522 AC: 1286 AN: 246456 AF XY: 0.00390

Gnomad AFR exome AF: 0.0587

Gnomad AMR exome AF: 0.00398

Gnomad ASJ exome AF: 0.00936

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000584

Gnomad OTH exome AF: 0.00445

GnomAD4 exome AF: 0.00220 AC: 3195 AN: 1449364 Hom.: 78 Cov.: 31 AF XY: 0.00200 AC XY: 1442 AN XY: 719590

African (AFR) AF: 0.0597 AC: 1990 AN: 33356

American (AMR) AF: 0.00462 AC: 206 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 278 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.000314 AC: 27 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48068

Middle Eastern (MID) AF: 0.00627 AC: 36 AN: 5742

European-Non Finnish (NFE) AF: 0.000328 AC: 363 AN: 1105938

Other (OTH) AF: 0.00491 AC: 295 AN: 60040

GnomAD4 genome AF: 0.0171 AC: 2601 AN: 152278 Hom.: 65 Cov.: 31 AF XY: 0.0164 AC XY: 1220 AN XY: 74470

African (AFR) AF: 0.0574 AC: 2385 AN: 41550

American (AMR) AF: 0.00804 AC: 123 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68016

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00911 Hom.: 10

Bravo AF: 0.0199

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	1	Colorectal cancer, susceptibility to, 12 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	11
DANN	Benign	0.46
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 38

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

Other links and lift over

dbSNP: rs75329753; hg19: chr12-133242049;