rs5744973

Variant names:

• chr12-132638010-G-A
• rs5744973
• NM_006231.4:c.5678+4C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-132638010-G-A
• chr12-132638010-G-C
• chr12-132638010-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006231.4(POLE):​c.5678+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,613,188 control chromosomes in the GnomAD database, including 104 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (57 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Scores: Splicing: ADA: 0.001402
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.0470

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-132638010-G-A is Benign according to our data. Variant chr12-132638010-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 221106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132638010-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1962/152190) while in subpopulation AFR AF= 0.0443 (1841/41514). AF 95% confidence interval is 0.0427. There are 47 homozygotes in gnomad4. There are 964 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 47 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.5678+4C>T		splice_region_variant, intron_variant	Intron 41 of 48	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5678+4C>T		splice_region_variant, intron_variant	Intron 41 of 47		XP_011533097.1
POLE	XM_011534797.4	c.4757+4C>T		splice_region_variant, intron_variant	Intron 33 of 39		XP_011533099.1
POLE	XM_011534802.4	c.2666+4C>T		splice_region_variant, intron_variant	Intron 17 of 23		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5678+4C>T		splice_region_variant, intron_variant	Intron 41 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1925 AN: 152072 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00349 AC: 877 AN: 250976 Hom.: 19 AF XY: 0.00257 AC XY: 348 AN XY: 135592

Gnomad AFR exome AF: 0.0462

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00149 AC: 2181 AN: 1460998 Hom.: 57 Cov.: 31 AF XY: 0.00132 AC XY: 961 AN XY: 726822

Gnomad4 AFR exome AF: 0.0466

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00424

GnomAD4 genome AF: 0.0129 AC: 1962 AN: 152190 Hom.: 47 Cov.: 32 AF XY: 0.0130 AC XY: 964 AN XY: 74404

Gnomad4 AFR AF: 0.0443

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00410 Hom.: 14

Bravo AF: 0.0149

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2016	Variant summary: The POLE c.5678+4C>T variant involves the alteration of a non-conserved nucleotide located in an intronic position outside of the canonical slice sites. Mutation taster predicts a benign outcome for this variant along with 4/5 in silico splice site tools predicting the variant not to have an impact on splicing. This variant was found in 550/121298 control chromosomes (16 homozygotes), predominantly observed in the African, 16 homozygotes subpopulation at a frequency of 0.0479531 (499/10406). This frequency is about 3376 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of African. In addition a clinical diagnostic laboratory classified this variant as Benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 17, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 09, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 27, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 10, 2017	- -

Colorectal cancer, susceptibility to, 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2016	- -

Polymerase proofreading-related adenomatous polyposis Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLE c.5678+4C>T variant was not identified in the literature. The variant was identified in dbSNP (ID: rs5744973) as "With Benign allele" and ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics, and four other clinical laboratories). The variant was identified in control databases in 1227 of 276680 chromosomes (23 homozygous) at a frequency of 0.004, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1091 of 24018 chromosomes (freq: 0.045), Other in 17 of 6462 chromosomes (freq: 0.003), Latino in 77 of 34402 chromosomes (freq: 0.002), European in 40 of 126262 chromosomes (freq: 0.0003), and South Asian in 2 of 30770 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The c.5678+4C>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.050
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5744973; hg19: chr12-133214596;