chr18-54274058-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 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

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36704665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLI	NM_007195.3	c.374C>G	p.Thr125Ser	missense_variant	Exon 3 of 10	ENST00000579534.6	NP_009126.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLI	ENST00000579534.6	c.374C>G	p.Thr125Ser	missense_variant	Exon 3 of 10	1	NM_007195.3	ENSP00000462664.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374C>G (p.T125S) alteration is located in exon 3 (coding exon 3) of the POLI gene. This alteration results from a C to G substitution at nucleotide position 374, causing the threonine (T) at amino acid position 125 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;.;T
Eigen	Benign	0.066
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;T;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	L;.;.;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	.;D;.;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.27	.;T;.;.;.;.
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.58	P;.;.;.;.;.
Vest4		0.16
MutPred		0.31		Gain of disorder (P = 0.0412);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-51800428;