rs199574832

Variant names:

• chr12-132649503-C-A
• rs199574832
• NM_006231.4:c.3808G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-132649503-C-A
• chr12-132649503-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.3808G>T​(p.Val1270Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1270I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.81
• Publications: 1 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: 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 (MetaRNN=0.029839128).
• BP6: Variant 12-132649503-C-A is Benign according to our data. Variant chr12-132649503-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3422156.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3808G>T	p.Val1270Phe	missense	Exon 31 of 49	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.3808G>T	p.Val1270Phe	missense	Exon 31 of 49	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.3727G>T	p.Val1243Phe	missense	Exon 30 of 48	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*3559G>T		non_coding_transcript_exon	Exon 31 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.000809 AC: 189 AN: 233676 AF XY: 0.000716

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.000997

Gnomad ASJ exome AF: 0.000733

Gnomad EAS exome AF: 0.00183

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.000690

Gnomad OTH exome AF: 0.000693

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000128 AC: 186 AN: 1454088 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 97 AN XY: 723218

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

African (AFR) AF: 0.0000602 AC: 2 AN: 33214

American (AMR) AF: 0.00127 AC: 55 AN: 43352

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25872

East Asian (EAS) AF: 0.00179 AC: 70 AN: 39146

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85924

European-Finnish (FIN) AF: 0.000533 AC: 27 AN: 50648

Middle Eastern (MID) AF: 0.000189 AC: 1 AN: 5284

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1110554

Other (OTH) AF: 0.0000666 AC: 4 AN: 60094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000572 Hom.: 0

ExAC AF: 0.00256 AC: 311

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.15
Sift	Benign	0.048	D
Sift4G	Uncertain	0.040	D
Polyphen		0.63	P
Vest4		0.70
MVP		0.58
MPC		0.31
ClinPred		0.037	T
GERP RS		5.7
Varity_R		0.40
gMVP		0.63
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs199574832; hg19: chr12-133226089; COSMIC: COSV57674799; COSMIC: COSV57674799;