rs5744807

Positions:

• chr12-132667035-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006231.4(POLE):​c.2319+468T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0244 in 152,266 control chromosomes in the GnomAD database, including 75 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 0.024 (75 hom., cov: 32)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0244 (3719/152266) while in subpopulation NFE AF= 0.0368 (2505/68014). AF 95% confidence interval is 0.0356. There are 75 homozygotes in gnomad4. There are 1806 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 75 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.2319+468T>C		intron_variant		ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.2319+468T>C		intron_variant		1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3720 AN: 152148 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00531

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0368

Gnomad OTH AF: 0.0196

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

GnomAD4 genome AF: 0.0244 AC: 3719 AN: 152266 Hom.: 75 Cov.: 32 AF XY: 0.0243 AC XY: 1806 AN XY: 74448

Gnomad4 AFR AF: 0.00529

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.0524

Gnomad4 NFE AF: 0.0368

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0331 Hom.: 38

Bravo AF: 0.0210

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.4
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5744807; hg19: chr12-133243621;