rs1555225931

Variant names:

• chr12-132660962-C-A
• rs1555225931
• NM_006231.4:c.3060+7G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-132660962-C-A
• chr12-132660962-C-G
• chr12-132660962-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006231.4(POLE):​c.3060+7G>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 0.00000125 in 1,595,234 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Scores: Splicing: ADA: 0.00008189
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.822
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-132660962-C-A is Benign according to our data. Variant chr12-132660962-C-A is described in CliVar as Likely_benign. Clinvar id is 540855.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-132660962-C-A is described in CliVar as Likely_benign. Clinvar id is 540855.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-132660962-C-A is described in CliVar as Likely_benign. Clinvar id is 540855.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-132660962-C-A is described in CliVar as Likely_benign. Clinvar id is 540855.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.3060+7G>T		splice_region_variant, intron_variant	Intron 25 of 48	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3060+7G>T		splice_region_variant, intron_variant	Intron 25 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443104 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 716314

African (AFR) AF: 0.00 AC: 0 AN: 32916

American (AMR) AF: 0.00 AC: 0 AN: 42420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 83800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102174

Other (OTH) AF: 0.00 AC: 0 AN: 59536

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.91
DANN	Benign	0.56
PhyloP100		0.82
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	0.000082
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: rs1555225931; hg19: chr12-133237548;