rs1060500840

Variant names:

• chr12-132661168-A-C
• rs1060500840
• NM_006231.4:c.2865-4T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-132661168-A-C
• chr12-132661168-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006231.4(POLE):​c.2865-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000717 in 139,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Scores: Splicing: ADA: 0.00007250
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.2865-4T>G		splice_region_variant, intron_variant	Intron 24 of 48	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.2865-4T>G		splice_region_variant, intron_variant	Intron 24 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000717 AC: 1 AN: 139384 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 68164

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 3356

American (AMR) AF: 0.00 AC: 0 AN: 2318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2480

East Asian (EAS) AF: 0.00 AC: 0 AN: 4768

South Asian (SAS) AF: 0.00 AC: 0 AN: 6762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 870

European-Non Finnish (NFE) AF: 0.00000935 AC: 1 AN: 107008

Other (OTH) AF: 0.00 AC: 0 AN: 5792

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.54
PhyloP100		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000072
dbscSNV1_RF	Benign	0.0
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: rs1060500840; hg19: chr12-133237754;