18-54294435-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 57 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=5.975265E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLI	NM_007195.3	MANE Select	c.2191G>A	p.Ala731Thr	missense	Exon 10 of 10	NP_009126.2
	POLI	NM_001351632.2		c.2116G>A	p.Ala706Thr	missense	Exon 10 of 10	NP_001338561.1
	POLI	NM_001351610.1		c.2065G>A	p.Ala689Thr	missense	Exon 9 of 9	NP_001338539.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLI	ENST00000579534.6	TSL:1 MANE Select	c.2191G>A	p.Ala731Thr	missense	Exon 10 of 10	ENSP00000462664.1
	POLI	ENST00000579434.5	TSL:1	c.1882G>A	p.Ala628Thr	missense	Exon 9 of 9	ENSP00000462681.1
	POLI	ENST00000585023.5	TSL:1	n.*1286G>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000463971.1

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

GnomAD2 exomes AF: 0.720 AC: 176904 AN: 245858 AF XY: 0.721

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 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

African (AFR) AF: 0.953 AC: 31568 AN: 33134

American (AMR) AF: 0.612 AC: 26750 AN: 43740

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 20565 AN: 25868

East Asian (EAS) AF: 0.734 AC: 29108 AN: 39640

South Asian (SAS) AF: 0.766 AC: 65269 AN: 85254

European-Finnish (FIN) AF: 0.717 AC: 38067 AN: 53112

Middle Eastern (MID) AF: 0.798 AC: 4579 AN: 5736

European-Non Finnish (NFE) AF: 0.694 AC: 770118 AN: 1109216

Other (OTH) AF: 0.731 AC: 43961 AN: 60112

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

African (AFR) AF: 0.943 AC: 39168 AN: 41534

American (AMR) AF: 0.684 AC: 10445 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 2745 AN: 3468

East Asian (EAS) AF: 0.713 AC: 3689 AN: 5176

South Asian (SAS) AF: 0.775 AC: 3737 AN: 4822

European-Finnish (FIN) AF: 0.736 AC: 7790 AN: 10584

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.701 AC: 47626 AN: 67948

Other (OTH) AF: 0.764 AC: 1611 AN: 2110

Alfa AF: 0.719 Hom.: 190561

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 v4.9

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
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.094	T
MetaRNN	Benign	6.0e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.63
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.030
Sift	Benign	0.89	T
Sift4G	Benign	0.79	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
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8305; hg19: chr18-51820805; COSMIC: COSV54188966; COSMIC: COSV54188966;