chr12-132649127-C-T

Variant names:

• chr12-132649127-C-T
• rs5744903
• NM_006231.4:c.4006-55G>A

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.4006-55G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 1,578,468 control chromosomes in the GnomAD database, including 5,170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (331 hom., cov: 33)
  • Exomes 𝑓: 0.079 (4839 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.495
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-132649127-C-T is Benign according to our data. Variant chr12-132649127-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.4006-55G>A		intron_variant	Intron 31 of 48	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.4006-55G>A		intron_variant	Intron 31 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 8561 AN: 152204 Hom.: 330 Cov.: 33

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.0967

Gnomad EAS AF: 0.0746

Gnomad SAS AF: 0.0311

Gnomad FIN AF: 0.0659

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0822

Gnomad OTH AF: 0.0487

GnomAD4 exome AF: 0.0786 AC: 112099 AN: 1426146 Hom.: 4839 Cov.: 31 AF XY: 0.0772 AC XY: 54410 AN XY: 704878

African (AFR) AF: 0.0117 AC: 384 AN: 32798

American (AMR) AF: 0.0304 AC: 1284 AN: 42220

Ashkenazi Jewish (ASJ) AF: 0.0964 AC: 2359 AN: 24470

East Asian (EAS) AF: 0.0795 AC: 3108 AN: 39114

South Asian (SAS) AF: 0.0315 AC: 2603 AN: 82644

European-Finnish (FIN) AF: 0.0669 AC: 3386 AN: 50616

Middle Eastern (MID) AF: 0.0597 AC: 268 AN: 4486

European-Non Finnish (NFE) AF: 0.0863 AC: 94119 AN: 1091168

Other (OTH) AF: 0.0783 AC: 4588 AN: 58630

GnomAD4 genome AF: 0.0562 AC: 8558 AN: 152322 Hom.: 331 Cov.: 33 AF XY: 0.0545 AC XY: 4060 AN XY: 74476

African (AFR) AF: 0.0134 AC: 559 AN: 41578

American (AMR) AF: 0.0357 AC: 546 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0967 AC: 335 AN: 3466

East Asian (EAS) AF: 0.0742 AC: 384 AN: 5178

South Asian (SAS) AF: 0.0311 AC: 150 AN: 4826

European-Finnish (FIN) AF: 0.0659 AC: 700 AN: 10628

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0822 AC: 5589 AN: 68022

Other (OTH) AF: 0.0496 AC: 105 AN: 2116

Alfa AF: 0.0674 Hom.: 473

Bravo AF: 0.0541

Asia WGS AF: 0.0610 AC: 214 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.36
PhyloP100		0.49
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: rs5744903; hg19: chr12-133225713;