chr18-54294435-G-C

Variant names:

• chr18-54294435-G-C
• rs8305
• NM_007195.3:c.2191G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007195.3(POLI):​c.2191G>C​(p.Ala731Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLI NM_007195.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.631
• Publications: 57 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09535316).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLI	NM_007195.3	MANE Select	c.2191G>C	p.Ala731Pro	missense	Exon 10 of 10	NP_009126.2
	POLI	NM_001351632.2		c.2116G>C	p.Ala706Pro	missense	Exon 10 of 10	NP_001338561.1
	POLI	NM_001351610.1		c.2065G>C	p.Ala689Pro	missense	Exon 9 of 9	NP_001338539.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLI	ENST00000579534.6	TSL:1 MANE Select	c.2191G>C	p.Ala731Pro	missense	Exon 10 of 10	ENSP00000462664.1
	POLI	ENST00000579434.5	TSL:1	c.1882G>C	p.Ala628Pro	missense	Exon 9 of 9	ENSP00000462681.1
	POLI	ENST00000585023.5	TSL:1	n.*1286G>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000463971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.86
DANN	Benign	0.77
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.28	N
PhyloP100		-0.63
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.10
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.057	T
Polyphen		0.80	P
Vest4		0.14
MutPred		0.33		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.50
MPC		0.013
ClinPred		0.30	T
GERP RS		-5.2
Varity_R		0.13
gMVP		0.22
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs8305; hg19: chr18-51820805;