rs7963858

Variant names:

• chr12-132630062-T-C
• rs7963858
• NM_006231.4:c.6330+2253A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-132630062-T-C
• chr12-132630062-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006231.4(POLE):​c.6330+2253A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.678 in 152,108 control chromosomes in the GnomAD database, including 35,107 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.68 (35107 hom., cov: 33)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 11 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.6330+2253A>G		intron	N/A	NP_006222.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	ENST00000320574.10	TSL:1 MANE Select	c.6330+2253A>G		intron	N/A	ENSP00000322570.5
	POLE	ENST00000535270.5	TSL:1	c.6249+2253A>G		intron	N/A	ENSP00000445753.1
	POLE	ENST00000537064.5	TSL:1	n.*6081+2253A>G		intron	N/A	ENSP00000442578.1

Frequencies

GnomAD3 genomes AF: 0.678 AC: 103014 AN: 151988 Hom.: 35084 Cov.: 33

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.678

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.678 AC: 103081 AN: 152108 Hom.: 35107 Cov.: 33 AF XY: 0.679 AC XY: 50497 AN XY: 74346

African (AFR) AF: 0.657 AC: 27248 AN: 41476

American (AMR) AF: 0.758 AC: 11585 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 2284 AN: 3472

East Asian (EAS) AF: 0.808 AC: 4184 AN: 5176

South Asian (SAS) AF: 0.678 AC: 3266 AN: 4814

European-Finnish (FIN) AF: 0.621 AC: 6568 AN: 10580

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.672 AC: 45676 AN: 67998

Other (OTH) AF: 0.680 AC: 1439 AN: 2116

Alfa AF: 0.676 Hom.: 49338

Bravo AF: 0.688

Asia WGS AF: 0.724 AC: 2515 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.22
DANN	Benign	0.22
PhyloP100		-1.0
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: rs7963858; hg19: chr12-133206648;