Genetic Variant POLI:p.Ile261Val (chr18-54280888-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007195.3(POLI):c.781A>G(p.Ile261Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,404,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. I261L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

POLI
NM_007195.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.833

Publications

3 publications found

Variant links:

Genes affected

POLI (HGNC:9182): (DNA polymerase iota) The protein encoded by this gene is an error-prone DNA polymerase involved in DNA repair. The encoded protein promotes DNA synthesis across lesions in the template DNA, which other polymerases cannot do. The encoded polymerase inserts deoxynucleotides across lesions and then relies on DNA polymerase zeta to extend the nascent DNA strand to bypass the lesion. [provided by RefSeq, May 2017]

POLI links:

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ACMG classification

Classification was made for transcript

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 (MetaRNN=0.056737304).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007195.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLI	NM_007195.3	MANE Select	c.781A>G	p.Ile261Val	missense	Exon 5 of 10	NP_009126.2	Q9UNA4
POLI	NM_001351632.2		c.706A>G	p.Ile236Val	missense	Exon 5 of 10	NP_001338561.1
POLI	NM_001351610.1		c.655A>G	p.Ile219Val	missense	Exon 4 of 9	NP_001338539.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLI	ENST00000579534.6	TSL:1 MANE Select	c.781A>G	p.Ile261Val	missense	Exon 5 of 10	ENSP00000462664.1	Q9UNA4
POLI	ENST00000579434.5	TSL:1	c.472A>G	p.Ile158Val	missense	Exon 4 of 9	ENSP00000462681.1	J3KSW2
POLI	ENST00000930897.1		c.628A>G	p.Ile210Val	missense	Exon 4 of 9	ENSP00000600956.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000800

AC:

AN:

250050

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1404384

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32276

American (AMR)

AF:

0.00

AC:

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25816

East Asian (EAS)

AF:

0.00

AC:

AN:

39440

South Asian (SAS)

AF:

0.00

AC:

AN:

85032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.000354

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

9.44e-7

AC:

AN:

1059792

Other (OTH)

AF:

0.00

AC:

AN:

58492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.056

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.68

M_CAP

Benign

0.0015

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

PhyloP100

0.83

PrimateAI

Benign

0.33

REVEL

Benign

0.062

Sift4G

Benign

0.75

Polyphen

0.0

Vest4

0.12

MutPred

0.63

Gain of methylation at K262 (P = 0.05)

MVP

0.36

MPC

0.013

ClinPred

0.35

GERP RS

0.43

Varity_R

0.028

gMVP

0.20

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over