rs73481453

Variant names:

• chr12-132624741-T-A
• rs73481453
• NM_006231.4:c.6817A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-132624741-T-A
• chr12-132624741-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006231.4(POLE):​c.6817A>T​(p.Thr2273Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000837 in 1,613,164 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2273I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (5 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.67
• Publications: 3 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=0.00729239).
• BP6: Variant 12-132624741-T-A is Benign according to our data. Variant chr12-132624741-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0042 (639/152076) while in subpopulation AFR AF = 0.0147 (608/41480). AF 95% confidence interval is 0.0137. There are 3 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.6817A>T	p.Thr2273Ser	missense	Exon 49 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.6817A>T	p.Thr2273Ser	missense	Exon 49 of 49	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.6736A>T	p.Thr2246Ser	missense	Exon 48 of 48	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*6568A>T		non_coding_transcript_exon	Exon 49 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 640 AN: 151958 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00480

GnomAD2 exomes AF: 0.00120 AC: 301 AN: 250960 AF XY: 0.00102

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000487 AC: 711 AN: 1461088 Hom.: 5 Cov.: 30 AF XY: 0.000400 AC XY: 291 AN XY: 726966

African (AFR) AF: 0.0159 AC: 532 AN: 33458

American (AMR) AF: 0.000805 AC: 36 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5756

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111348

Other (OTH) AF: 0.00147 AC: 89 AN: 60368

GnomAD4 genome AF: 0.00420 AC: 639 AN: 152076 Hom.: 3 Cov.: 33 AF XY: 0.00424 AC XY: 315 AN XY: 74358

African (AFR) AF: 0.0147 AC: 608 AN: 41480

American (AMR) AF: 0.00118 AC: 18 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67956

Other (OTH) AF: 0.00475 AC: 10 AN: 2106

Alfa AF: 0.000717 Hom.: 2

Bravo AF: 0.00505

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00152 AC: 184

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Colorectal cancer, susceptibility to, 12 (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.058
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.15
Sift	Benign	0.10	T
Sift4G	Benign	0.063	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.52		Gain of catalytic residue at L2274 (P = 5e-04)
MVP		0.33
MPC		0.17
ClinPred		0.043	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.14
gMVP		0.36
Mutation Taster		=71/29	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: rs73481453; hg19: chr12-133201327;