chr18-54293839-T-C

Variant names:

• chr18-54293839-T-C
• rs3218786
• NM_007195.3:c.1595T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_007195.3(POLI):​c.1595T>C​(p.Phe532Ser) variant causes a missense change. The variant allele was found at a frequency of 0.028 in 1,610,050 control chromosomes in the GnomAD database, including 746 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.022 (53 hom., cov: 32)
  • Exomes 𝑓: 0.029 (693 hom.)
• Consequence: POLI NM_007195.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.71
• Publications: 18 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070573986).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0222 (3382/152238) while in subpopulation NFE AF = 0.0323 (2196/67974). AF 95% confidence interval is 0.0312. There are 53 homozygotes in GnomAd4. There are 1595 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 gene

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.1595T>C	p.Phe532Ser	missense	Exon 10 of 10	NP_009126.2
	POLI	NM_001351632.2		c.1520T>C	p.Phe507Ser	missense	Exon 10 of 10	NP_001338561.1
	POLI	NM_001351610.1		c.1469T>C	p.Phe490Ser	missense	Exon 9 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.1595T>C	p.Phe532Ser	missense	Exon 10 of 10	ENSP00000462664.1
	POLI	ENST00000579434.5	TSL:1	c.1286T>C	p.Phe429Ser	missense	Exon 9 of 9	ENSP00000462681.1
	POLI	ENST00000585023.5	TSL:1	n.*690T>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000463971.1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3385 AN: 152120 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0234 AC: 5736 AN: 244740 AF XY: 0.0235

Gnomad AFR exome AF: 0.00514

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0508

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.0334

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0286 AC: 41733 AN: 1457812 Hom.: 693 Cov.: 31 AF XY: 0.0281 AC XY: 20403 AN XY: 724942

African (AFR) AF: 0.00434 AC: 145 AN: 33410

American (AMR) AF: 0.0108 AC: 478 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.0489 AC: 1272 AN: 26038

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39594

South Asian (SAS) AF: 0.00524 AC: 450 AN: 85810

European-Finnish (FIN) AF: 0.0384 AC: 2044 AN: 53284

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5764

European-Non Finnish (NFE) AF: 0.0321 AC: 35572 AN: 1109454

Other (OTH) AF: 0.0266 AC: 1602 AN: 60240

GnomAD4 genome AF: 0.0222 AC: 3382 AN: 152238 Hom.: 53 Cov.: 32 AF XY: 0.0214 AC XY: 1595 AN XY: 74434

African (AFR) AF: 0.00563 AC: 234 AN: 41556

American (AMR) AF: 0.0137 AC: 210 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 179 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4824

European-Finnish (FIN) AF: 0.0413 AC: 439 AN: 10622

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0323 AC: 2196 AN: 67974

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0304 Hom.: 345

Bravo AF: 0.0206

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0338 AC: 291

ExAC AF: 0.0232 AC: 2810

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.58
MPC		0.096
ClinPred		0.017	T
GERP RS		5.5
Varity_R		0.78
gMVP		0.63
Mutation Taster		=71/29	polymorphism (auto)

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

dbSNP: rs3218786; hg19: chr18-51820209; COSMIC: COSV107255602; COSMIC: COSV107255602;