12-132657119-T-C

Variant names:

• chr12-132657119-T-C
• rs5744889
• NM_006231.4:c.3582+17A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006231.4(POLE):​c.3582+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.964 in 1,613,426 control chromosomes in the GnomAD database, including 750,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72246 hom., cov: 29)
  • Exomes 𝑓: 0.96 (678149 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.11
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 12-132657119-T-C is Benign according to our data. Variant chr12-132657119-T-C is described in ClinVar as Benign. ClinVar VariationId is 380211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.3582+17A>G		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.3582+17A>G		intron	N/A	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.3501+17A>G		intron	N/A	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*3333+17A>G		intron	N/A	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.975 AC: 148139 AN: 152010 Hom.: 72185 Cov.: 29

Gnomad AFR AF: 0.993

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.973

Gnomad ASJ AF: 0.984

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.972

Gnomad FIN AF: 0.965

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.963

Gnomad OTH AF: 0.968

GnomAD2 exomes AF: 0.971 AC: 243962 AN: 251156 AF XY: 0.971

Gnomad AFR exome AF: 0.993

Gnomad AMR exome AF: 0.974

Gnomad ASJ exome AF: 0.982

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.964

Gnomad NFE exome AF: 0.965

Gnomad OTH exome AF: 0.971

GnomAD4 exome AF: 0.963 AC: 1407674 AN: 1461298 Hom.: 678149 Cov.: 45 AF XY: 0.964 AC XY: 700595 AN XY: 726938

African (AFR) AF: 0.994 AC: 33281 AN: 33476

American (AMR) AF: 0.974 AC: 43575 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.984 AC: 25714 AN: 26128

East Asian (EAS) AF: 1.00 AC: 39679 AN: 39686

South Asian (SAS) AF: 0.965 AC: 83181 AN: 86242

European-Finnish (FIN) AF: 0.963 AC: 51273 AN: 53224

Middle Eastern (MID) AF: 0.984 AC: 5666 AN: 5756

European-Non Finnish (NFE) AF: 0.960 AC: 1066876 AN: 1111698

Other (OTH) AF: 0.968 AC: 58429 AN: 60372

GnomAD4 genome AF: 0.975 AC: 148259 AN: 152128 Hom.: 72246 Cov.: 29 AF XY: 0.975 AC XY: 72472 AN XY: 74348

African (AFR) AF: 0.993 AC: 41178 AN: 41484

American (AMR) AF: 0.973 AC: 14876 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.984 AC: 3416 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5157 AN: 5160

South Asian (SAS) AF: 0.972 AC: 4677 AN: 4810

European-Finnish (FIN) AF: 0.965 AC: 10222 AN: 10590

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.963 AC: 65499 AN: 68012

Other (OTH) AF: 0.969 AC: 2045 AN: 2110

Alfa AF: 0.973 Hom.: 13367

Bravo AF: 0.976

Asia WGS AF: 0.986 AC: 3428 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Colorectal cancer, susceptibility to, 12 (1)
-	-	1	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.30
DANN	Benign	0.31
PhyloP100		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs5744889; hg19: chr12-133233705;