18-54269655-T-C

Variant names:

• chr18-54269655-T-C
• rs200801352
• NM_007195.3:c.109T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007195.3(POLI):​c.109T>C​(p.Ser37Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 1,353,604 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S37T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: POLI NM_007195.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.436
• 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]

ENSG00000277324 (HGNC:):

ACMG classification

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=0.066205025).

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.109T>C	p.Ser37Pro	missense	Exon 1 of 10	NP_009126.2	Q9UNA4
	POLI	NM_001351632.2		c.34T>C	p.Ser12Pro	missense	Exon 1 of 10	NP_001338561.1
	POLI	NM_001351610.1		c.109T>C	p.Ser37Pro	missense	Exon 1 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.109T>C	p.Ser37Pro	missense	Exon 1 of 10	ENSP00000462664.1	Q9UNA4
	POLI	ENST00000579434.5	TSL:1	c.-446T>C		5_prime_UTR	Exon 1 of 9	ENSP00000462681.1	J3KSW2
	POLI	ENST00000930897.1		c.109T>C	p.Ser37Pro	missense	Exon 1 of 9	ENSP00000600956.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000222 AC: 3 AN: 1353604 Hom.: 0 Cov.: 34 AF XY: 0.00000300 AC XY: 2 AN XY: 667706

African (AFR) AF: 0.00 AC: 0 AN: 27286

American (AMR) AF: 0.00 AC: 0 AN: 29930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23816

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 76600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4806

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1062914

Other (OTH) AF: 0.00 AC: 0 AN: 56086

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.78
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.44
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.051
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.21	B
Vest4		0.12
MutPred		0.29		Loss of glycosylation at S37 (P = 0.0568)
MVP		0.31
MPC		0.015
ClinPred		0.16	T
GERP RS		1.6
PromoterAI		-0.022	Neutral
Varity_R		0.12
gMVP		0.24
Mutation Taster		=94/6	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: rs200801352; hg19: chr18-51796025;