rs34047482

Variant names:

• chr12-132681251-C-A
• rs34047482
• NM_006231.4:c.91G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-132681251-C-A
• chr12-132681251-C-G
• chr12-132681251-C-T

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.91G>T​(p.Ala31Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,614,170 control chromosomes in the GnomAD database, including 421 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A31V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (26 hom., cov: 32)
  • Exomes 𝑓: 0.020 (395 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 7.41
• Publications: 14 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=0.0056500733).
• BP6: Variant 12-132681251-C-A is Benign according to our data. Variant chr12-132681251-C-A is described in ClinVar as Benign. ClinVar VariationId is 221182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0131 (1997/152322) while in subpopulation NFE AF = 0.0211 (1438/68022). AF 95% confidence interval is 0.0202. There are 26 homozygotes in GnomAd4. There are 925 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR,AD 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.91G>T	p.Ala31Ser	missense	Exon 2 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.91G>T	p.Ala31Ser	missense	Exon 2 of 49	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.91G>T	p.Ala31Ser	missense	Exon 2 of 48	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.91G>T		non_coding_transcript_exon	Exon 2 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1998 AN: 152204 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00453

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.0124 AC: 3113 AN: 251414 AF XY: 0.0129

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00748

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0204 AC: 29851 AN: 1461848 Hom.: 395 Cov.: 31 AF XY: 0.0202 AC XY: 14680 AN XY: 727224

African (AFR) AF: 0.00332 AC: 111 AN: 33478

American (AMR) AF: 0.00664 AC: 297 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0102 AC: 882 AN: 86258

European-Finnish (FIN) AF: 0.00794 AC: 424 AN: 53402

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.0244 AC: 27129 AN: 1111992

Other (OTH) AF: 0.0156 AC: 940 AN: 60394

GnomAD4 genome AF: 0.0131 AC: 1997 AN: 152322 Hom.: 26 Cov.: 32 AF XY: 0.0124 AC XY: 925 AN XY: 74496

African (AFR) AF: 0.00452 AC: 188 AN: 41578

American (AMR) AF: 0.0136 AC: 208 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4826

European-Finnish (FIN) AF: 0.00829 AC: 88 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1438 AN: 68022

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0187 Hom.: 113

Bravo AF: 0.0134

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0236 AC: 91

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0220 AC: 189

ExAC AF: 0.0122 AC: 1485

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	not provided (6)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	2	Colorectal cancer, susceptibility to, 12 (2)
-	-	1	Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.20
Sift	Benign	0.44	T
Sift4G	Benign	0.69	T
Polyphen		0.0040	B
Vest4		0.39
MPC		0.18
ClinPred		0.043	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.37
Mutation Taster		=96/4	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: rs34047482; hg19: chr12-133257837;