chr18-54274058-C-G

Variant names:

• chr18-54274058-C-G
• NM_007195.3:c.374C>G

Variant summary

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

The NM_007195.3(POLI):​c.374C>G​(p.Thr125Ser) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLI NM_007195.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.43
• 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=0.36704665).

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.374C>G	p.Thr125Ser	missense	Exon 3 of 10	NP_009126.2	Q9UNA4
	POLI	NM_001351632.2		c.299C>G	p.Thr100Ser	missense	Exon 3 of 10	NP_001338561.1
	POLI	NM_001351610.1		c.248C>G	p.Thr83Ser	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.374C>G	p.Thr125Ser	missense	Exon 3 of 10	ENSP00000462664.1	Q9UNA4
	POLI	ENST00000579434.5	TSL:1	c.65C>G	p.Thr22Ser	missense	Exon 2 of 9	ENSP00000462681.1	J3KSW2
	POLI	ENST00000930897.1		c.374C>G	p.Thr125Ser	missense	Exon 3 of 9	ENSP00000600956.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.066
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.24
Sift	Benign	0.27	T
Sift4G	Benign	0.12	T
Polyphen		0.58	P
Vest4		0.16
MutPred		0.31		Gain of disorder (P = 0.0412)
MVP		0.77
MPC		0.021
ClinPred		0.79	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.27
Mutation Taster		=40/60	disease causing

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

Other links and lift over

hg19: chr18-51800428;