rs5744751

Variant names:

• chr12-132677409-G-A
• rs5744751
• NM_006231.4:c.755C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-132677409-G-A
• chr12-132677409-G-C

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.755C>T​(p.Ala252Val) variant causes a missense change. The variant allele was found at a frequency of 0.0991 in 1,613,392 control chromosomes in the GnomAD database, including 8,666 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A252P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.077 (602 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8064 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.64
• Publications: 48 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 (MetaRNN=0.0018293858).
• BP6: Variant 12-132677409-G-A is Benign according to our data. Variant chr12-132677409-G-A is described in ClinVar as Benign. ClinVar VariationId is 380210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 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.755C>T	p.Ala252Val	missense	Exon 8 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.755C>T	p.Ala252Val	missense	Exon 8 of 49	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.674C>T	p.Ala225Val	missense	Exon 7 of 48	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.755C>T		non_coding_transcript_exon	Exon 8 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.0770 AC: 11705 AN: 152046 Hom.: 602 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.0543

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0576

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0684

GnomAD2 exomes AF: 0.0860 AC: 21621 AN: 251472 AF XY: 0.0872

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.0423

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.101 AC: 148220 AN: 1461228 Hom.: 8064 Cov.: 32 AF XY: 0.100 AC XY: 72931 AN XY: 726958

African (AFR) AF: 0.0153 AC: 511 AN: 33480

American (AMR) AF: 0.0432 AC: 1931 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2927 AN: 26126

East Asian (EAS) AF: 0.109 AC: 4315 AN: 39694

South Asian (SAS) AF: 0.0530 AC: 4570 AN: 86250

European-Finnish (FIN) AF: 0.108 AC: 5788 AN: 53400

Middle Eastern (MID) AF: 0.0673 AC: 388 AN: 5766

European-Non Finnish (NFE) AF: 0.110 AC: 121816 AN: 1111422

Other (OTH) AF: 0.0990 AC: 5974 AN: 60368

GnomAD4 genome AF: 0.0769 AC: 11700 AN: 152164 Hom.: 602 Cov.: 32 AF XY: 0.0760 AC XY: 5650 AN XY: 74380

African (AFR) AF: 0.0177 AC: 736 AN: 41522

American (AMR) AF: 0.0542 AC: 828 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3468

East Asian (EAS) AF: 0.102 AC: 526 AN: 5174

South Asian (SAS) AF: 0.0572 AC: 276 AN: 4822

European-Finnish (FIN) AF: 0.107 AC: 1136 AN: 10594

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7457 AN: 67990

Other (OTH) AF: 0.0691 AC: 146 AN: 2112

Alfa AF: 0.0967 Hom.: 2597

Bravo AF: 0.0713

Asia WGS AF: 0.100 AC: 346 AN: 3478

EpiCase AF: 0.101

EpiControl AF: 0.102

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
PhyloP100		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.35
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5744751; hg19: chr12-133253995; COSMIC: COSV57678718; COSMIC: COSV57678718;