chr18-54293839-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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 Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 53 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLI	NM_007195.3	c.1595T>C	p.Phe532Ser	missense_variant	Exon 10 of 10	ENST00000579534.6	NP_009126.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLI	ENST00000579534.6	c.1595T>C	p.Phe532Ser	missense_variant	Exon 10 of 10	1	NM_007195.3	ENSP00000462664.1

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

GnomAD3 exomes AF: 0.0234 AC: 5736 AN: 244740 Hom.: 112 AF XY: 0.0235 AC XY: 3112 AN XY: 132196

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 SAS exome AF: 0.00496

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

Gnomad4 AFR exome AF: 0.00434

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.0489

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00524

Gnomad4 FIN exome AF: 0.0384

Gnomad4 NFE exome AF: 0.0321

Gnomad4 OTH exome AF: 0.0266

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

Gnomad4 AFR AF: 0.00563

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.0516

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0413

Gnomad4 NFE AF: 0.0323

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0317 Hom.: 190

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 v4.3

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;T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;D;D;T
MetaRNN	Benign	0.0071	T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.1	M;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	.;D;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.010	.;D;.;.
Sift4G	Uncertain	0.0030	D;D;D;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

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

LitVar

Other links and lift over

dbSNP: rs3218786; hg19: chr18-51820209;