18-54274061-G-T

Variant names:

• chr18-54274061-G-T
• rs759745970
• NM_007195.3:c.377G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007195.3(POLI):​c.377G>T​(p.Arg126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000744 in 1,344,478 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R126P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: POLI NM_007195.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3767122).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLI	NM_007195.3	MANE Select	c.377G>T	p.Arg126Leu	missense	Exon 3 of 10	NP_009126.2	Q9UNA4
	POLI	NM_001351632.2		c.302G>T	p.Arg101Leu	missense	Exon 3 of 10	NP_001338561.1
	POLI	NM_001351610.1		c.251G>T	p.Arg84Leu	missense	Exon 2 of 9	NP_001338539.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLI	ENST00000579534.6	TSL:1 MANE Select	c.377G>T	p.Arg126Leu	missense	Exon 3 of 10	ENSP00000462664.1	Q9UNA4
	POLI	ENST00000579434.5	TSL:1	c.68G>T	p.Arg23Leu	missense	Exon 2 of 9	ENSP00000462681.1	J3KSW2
	POLI	ENST00000930897.1		c.377G>T	p.Arg126Leu	missense	Exon 3 of 9	ENSP00000600956.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.44e-7 AC: 1 AN: 1344478 Hom.: 0 Cov.: 27 AF XY: 0.00000150 AC XY: 1 AN XY: 666258

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

African (AFR) AF: 0.00 AC: 0 AN: 28832

American (AMR) AF: 0.00 AC: 0 AN: 31598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22782

East Asian (EAS) AF: 0.00 AC: 0 AN: 34718

South Asian (SAS) AF: 0.0000152 AC: 1 AN: 65852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5348

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051486

Other (OTH) AF: 0.00 AC: 0 AN: 54694

⚠️ 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.099
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	-0.11	N
PhyloP100		1.2
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.44
Sift	Benign	0.076	T
Sift4G	Benign	0.26	T
Polyphen		0.99	D
Vest4		0.36
MutPred		0.59		Loss of disorder (P = 0.0786)
MVP		0.73
MPC		0.016
ClinPred		0.92	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.53
gMVP		0.42
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs759745970; hg19: chr18-51800431;