rs3730477

Positions:

• chr10-101580299-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001174084.2(POLL):​c.1312C>T​(p.Arg438Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,613,192 control chromosomes in the GnomAD database, including 33,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2392 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31057 hom.)
• Consequence: POLL NM_001174084.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.72

Genes affected

POLL (HGNC:9184): (DNA polymerase lambda) This gene encodes a DNA polymerase. DNA polymerases catalyze DNA-template-directed extension of the 3'-end of a DNA strand. This particular polymerase, which is a member of the X family of DNA polymerases, likely plays a role in non-homologous end joining and other DNA repair processes. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2010]

DPCD (HGNC:24542): (deleted in primary ciliary dyskinesia homolog (mouse)) This gene in mouse encodes a protein that may be involved in the generation and maintenance of ciliated cells. In mouse, expression of this gene increases during ciliated cell differentiation, and disruption of this gene has been linked to primary ciliary dyskinesia. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017029941).
• BP6: Variant 10-101580299-G-A is Benign according to our data. Variant chr10-101580299-G-A is described in ClinVar as [Benign]. Clinvar id is 1248188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLL	NM_001174084.2	c.1312C>T	p.Arg438Trp	missense_variant	8/9	ENST00000370162.8	NP_001167555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLL	ENST00000370162.8	c.1312C>T	p.Arg438Trp	missense_variant	8/9	1	NM_001174084.2	ENSP00000359181	P1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24444 AN: 152030 Hom.: 2393 Cov.: 32

Gnomad AFR AF: 0.0693

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.0359

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.172

GnomAD3 exomes AF: 0.168 AC: 42107 AN: 251244 Hom.: 4191 AF XY: 0.171 AC XY: 23283 AN XY: 135806

Gnomad AFR exome AF: 0.0671

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.0330

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.200 AC: 292446 AN: 1461044 Hom.: 31057 Cov.: 33 AF XY: 0.199 AC XY: 144760 AN XY: 726862

Gnomad4 AFR exome AF: 0.0621

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.240

Gnomad4 EAS exome AF: 0.0468

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.190

GnomAD4 genome AF: 0.161 AC: 24434 AN: 152148 Hom.: 2392 Cov.: 32 AF XY: 0.158 AC XY: 11723 AN XY: 74372

Gnomad4 AFR AF: 0.0692

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.0360

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.171

Alfa AF: 0.209 Hom.: 8454

Bravo AF: 0.156

TwinsUK AF: 0.216 AC: 801

ALSPAC AF: 0.208 AC: 803

ESP6500AA AF: 0.0742 AC: 327

ESP6500EA AF: 0.228 AC: 1964

ExAC AF: 0.168 AC: 20336

Asia WGS AF: 0.0620 AC: 215 AN: 3478

EpiCase AF: 0.231

EpiControl AF: 0.224

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 19806195, 20693240) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T;T;.;T;T;.;T;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;.;T;.;D;T;D;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;M;.;M;.;.;M;.;.
MutationTaster	Benign	8.6e-12	P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;.;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.016	D;D;D;D;D;.;D;T;D
Sift4G	Uncertain	0.034	D;D;D;D;D;D;D;.;D
Polyphen		1.0	D;D;D;D;.;.;D;.;.
Vest4		0.13
MPC		0.18
ClinPred		0.042	T
GERP RS		1.7
Varity_R		0.28
gMVP		0.48

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: rs3730477; hg19: chr10-103340056; COSMIC: COSV54574388; COSMIC: COSV54574388;