NM_006231.4:c.4444+4T>A

Variant names:

• chr12-132643403-A-T
• rs5744941
• NM_006231.4:c.4444+4T>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.4444+4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 1,614,164 control chromosomes in the GnomAD database, including 5,271 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (329 hom., cov: 34)
  • Exomes 𝑓: 0.078 (4942 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002649
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.304
• Publications: 12 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 (BayesDel_noAF=-0.72).
• BP6: Variant 12-132643403-A-T is Benign according to our data. Variant chr12-132643403-A-T is described in ClinVar as Benign. ClinVar VariationId is 380213.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.

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.4444+4T>A		splice_region intron	N/A	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.4444+4T>A		splice_region intron	N/A	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.4363+4T>A		splice_region intron	N/A	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*4195+4T>A		splice_region intron	N/A	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 8564 AN: 152194 Hom.: 328 Cov.: 34

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0658

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0822

Gnomad OTH AF: 0.0488

GnomAD2 exomes AF: 0.0624 AC: 15693 AN: 251402 AF XY: 0.0631

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.0305

Gnomad ASJ exome AF: 0.0970

Gnomad EAS exome AF: 0.0749

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.0813

Gnomad OTH exome AF: 0.0762

GnomAD4 exome AF: 0.0784 AC: 114555 AN: 1461852 Hom.: 4942 Cov.: 37 AF XY: 0.0769 AC XY: 55936 AN XY: 727232

African (AFR) AF: 0.0117 AC: 392 AN: 33480

American (AMR) AF: 0.0308 AC: 1379 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0952 AC: 2488 AN: 26136

East Asian (EAS) AF: 0.0798 AC: 3168 AN: 39700

South Asian (SAS) AF: 0.0316 AC: 2722 AN: 86256

European-Finnish (FIN) AF: 0.0666 AC: 3559 AN: 53400

Middle Eastern (MID) AF: 0.0569 AC: 328 AN: 5768

European-Non Finnish (NFE) AF: 0.0862 AC: 95809 AN: 1111994

Other (OTH) AF: 0.0780 AC: 4710 AN: 60396

GnomAD4 genome AF: 0.0562 AC: 8561 AN: 152312 Hom.: 329 Cov.: 34 AF XY: 0.0545 AC XY: 4059 AN XY: 74480

African (AFR) AF: 0.0135 AC: 562 AN: 41582

American (AMR) AF: 0.0357 AC: 546 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 336 AN: 3472

East Asian (EAS) AF: 0.0741 AC: 384 AN: 5180

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4826

European-Finnish (FIN) AF: 0.0658 AC: 699 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0822 AC: 5588 AN: 68004

Other (OTH) AF: 0.0497 AC: 105 AN: 2114

Alfa AF: 0.0755 Hom.: 152

Bravo AF: 0.0542

Asia WGS AF: 0.0610 AC: 214 AN: 3478

EpiCase AF: 0.0785

EpiControl AF: 0.0792

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Colorectal cancer, susceptibility to, 12 (1)
-	-	1	POLE-related polyposis and colorectal cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.5
DANN	Benign	0.69
PhyloP100		0.30
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0060
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: rs5744941; hg19: chr12-133219989;