rs199574832

chr12-132649503-C-Achr12-132649503-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006231.4(POLE):c.3808G>T(p.Val1270Phe) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029839128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.3808G>T	p.Val1270Phe	missense_variant	31/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.3808G>T	p.Val1270Phe	missense_variant	31/49	1	NM_006231.4	P1

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

Not reported in ClinVar

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;.
MutationTaster	Benign	1.0	D;D;D
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;