chr18-54294435-G-A

Variant names:

• chr18-54294435-G-A
• rs8305
• NM_007195.3:c.2191G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007195.3(POLI):​c.2191G>A​(p.Ala731Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 1,607,918 control chromosomes in the GnomAD database, including 412,972 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.77 (46386 hom., cov: 32)
  • Exomes 𝑓: 0.71 (366586 hom.)
• Consequence: POLI NM_007195.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.631

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=5.975265E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLI	NM_007195.3	c.2191G>A	p.Ala731Thr	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.2191G>A	p.Ala731Thr	missense_variant	Exon 10 of 10	1	NM_007195.3	ENSP00000462664.1

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117549 AN: 151988 Hom.: 46335 Cov.: 32

Gnomad AFR AF: 0.943

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.686

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.763

GnomAD3 exomes AF: 0.720 AC: 176904 AN: 245858 Hom.: 64556 AF XY: 0.721 AC XY: 95905 AN XY: 133008

Gnomad AFR exome AF: 0.947

Gnomad AMR exome AF: 0.602

Gnomad ASJ exome AF: 0.805

Gnomad EAS exome AF: 0.720

Gnomad SAS exome AF: 0.769

Gnomad FIN exome AF: 0.719

Gnomad NFE exome AF: 0.702

Gnomad OTH exome AF: 0.710

GnomAD4 exome AF: 0.707 AC: 1029985 AN: 1455812 Hom.: 366586 Cov.: 35 AF XY: 0.709 AC XY: 513453 AN XY: 723990

Gnomad4 AFR exome AF: 0.953

Gnomad4 AMR exome AF: 0.612

Gnomad4 ASJ exome AF: 0.795

Gnomad4 EAS exome AF: 0.734

Gnomad4 SAS exome AF: 0.766

Gnomad4 FIN exome AF: 0.717

Gnomad4 NFE exome AF: 0.694

Gnomad4 OTH exome AF: 0.731

GnomAD4 genome AF: 0.773 AC: 117645 AN: 152106 Hom.: 46386 Cov.: 32 AF XY: 0.774 AC XY: 57549 AN XY: 74342

Gnomad4 AFR AF: 0.943

Gnomad4 AMR AF: 0.684

Gnomad4 ASJ AF: 0.792

Gnomad4 EAS AF: 0.713

Gnomad4 SAS AF: 0.775

Gnomad4 FIN AF: 0.736

Gnomad4 NFE AF: 0.701

Gnomad4 OTH AF: 0.764

Alfa AF: 0.711 Hom.: 92487

Bravo AF: 0.773

TwinsUK AF: 0.691 AC: 2563

ALSPAC AF: 0.690 AC: 2660

ESP6500AA AF: 0.932 AC: 4108

ESP6500EA AF: 0.699 AC: 6008

ExAC AF: 0.726 AC: 88161

Asia WGS AF: 0.755 AC: 2628 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.034
DANN	Benign	0.57
DEOGEN2	Benign	0.025	T;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.094	T;T;T;T
MetaRNN	Benign	6.0e-7	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.42	.;N;.;.
REVEL	Benign	0.030
Sift	Benign	0.89	.;T;.;.
Sift4G	Benign	0.79	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.033
MPC		0.013
ClinPred		0.0025	T
GERP RS		-5.2
Varity_R		0.016
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8305; hg19: chr18-51820805; COSMIC: COSV54188966; COSMIC: COSV54188966;