12-132659414-C-T

Variant names:

• chr12-132659414-C-T
• rs5744857
• NM_006231.4:c.3156G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006231.4(POLE):​c.3156G>A​(p.Thr1052Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,613,846 control chromosomes in the GnomAD database, including 179,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1052T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.54 (23133 hom., cov: 33)
  • Exomes 𝑓: 0.46 (156015 hom.)
• Consequence: POLE NM_006231.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.20
• Publications: 32 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 12-132659414-C-T is Benign according to our data. Variant chr12-132659414-C-T is described in ClinVar as Benign. ClinVar VariationId is 380212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 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.3156G>A	p.Thr1052Thr	synonymous	Exon 26 of 49	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.3156G>A	p.Thr1052Thr	synonymous	Exon 26 of 49	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.3075G>A	p.Thr1025Thr	synonymous	Exon 25 of 48	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*2203G>A		non_coding_transcript_exon	Exon 26 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81396 AN: 152042 Hom.: 23086 Cov.: 33

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.528

GnomAD2 exomes AF: 0.503 AC: 126545 AN: 251400 AF XY: 0.496

Gnomad AFR exome AF: 0.716

Gnomad AMR exome AF: 0.578

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.705

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.476

GnomAD4 exome AF: 0.457 AC: 667281 AN: 1461686 Hom.: 156015 Cov.: 47 AF XY: 0.459 AC XY: 333403 AN XY: 727144

African (AFR) AF: 0.716 AC: 23959 AN: 33476

American (AMR) AF: 0.572 AC: 25579 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10185 AN: 26134

East Asian (EAS) AF: 0.697 AC: 27683 AN: 39700

South Asian (SAS) AF: 0.546 AC: 47106 AN: 86254

European-Finnish (FIN) AF: 0.427 AC: 22806 AN: 53392

Middle Eastern (MID) AF: 0.518 AC: 2990 AN: 5768

European-Non Finnish (NFE) AF: 0.430 AC: 478527 AN: 1111848

Other (OTH) AF: 0.471 AC: 28446 AN: 60394

GnomAD4 genome AF: 0.536 AC: 81493 AN: 152160 Hom.: 23133 Cov.: 33 AF XY: 0.537 AC XY: 39967 AN XY: 74386

African (AFR) AF: 0.715 AC: 29695 AN: 41510

American (AMR) AF: 0.555 AC: 8480 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1328 AN: 3466

East Asian (EAS) AF: 0.701 AC: 3636 AN: 5186

South Asian (SAS) AF: 0.558 AC: 2691 AN: 4824

European-Finnish (FIN) AF: 0.433 AC: 4585 AN: 10596

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29516 AN: 67972

Other (OTH) AF: 0.531 AC: 1121 AN: 2112

Alfa AF: 0.466 Hom.: 27098

Bravo AF: 0.551

Asia WGS AF: 0.590 AC: 2050 AN: 3478

EpiCase AF: 0.433

EpiControl AF: 0.430

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Colorectal cancer, susceptibility to, 12 (1)
-	-	1	Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (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	-0.61
CADD	Benign	1.9
DANN	Benign	0.50
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=78/22	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: rs5744857; hg19: chr12-133236000; COSMIC: COSV105207436;