chr12-132649503-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. 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 (★).

• 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

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 Likely_benign. Variant got -6 ACMG points.

• 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 id is 3422156.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.3808G>T	p.Val1270Phe	missense_variant	Exon 31 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3808G>T	p.Val1270Phe	missense_variant	Exon 31 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.000809 AC: 189 AN: 233676 Hom.: 0 AF XY: 0.000716 AC XY: 92 AN XY: 128558

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 SAS exome AF: 0.000165

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

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.00179

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.000533

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000541 Hom.: 0

ExAC AF: 0.00256 AC: 311

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Oct 28, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

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;D
MetaRNN	Benign	0.030	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.15
Sift	Benign	0.048	D;D
Sift4G	Uncertain	0.040	D;D
Polyphen		0.63	P;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs199574832; hg19: chr12-133226089; COSMIC: COSV57674799; COSMIC: COSV57674799;