10-101580253-T-C

Position:

• chr10-101580253-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001174084.2(POLL):​c.1358A>G​(p.Gln453Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLL NM_001174084.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07482615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLL	NM_001174084.2	c.1358A>G	p.Gln453Arg	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.1358A>G	p.Gln453Arg	missense_variant	8/9	1	NM_001174084.2	ENSP00000359181	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.1358A>G (p.Q453R) alteration is located in exon 8 (coding exon 7) of the POLL gene. This alteration results from a A to G substitution at nucleotide position 1358, causing the glutamine (Q) at amino acid position 453 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.70
DEOGEN2	Benign	0.013	T;T;.;T;T;.;T;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T;.;T;.;T;T;T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.075	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;L;.;L;.;.;L;.;.
MutationTaster	Benign	0.50	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N;N;N;N;N;.;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.24	T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T;T;T;.;T
Polyphen		0.0	B;B;B;B;.;.;B;.;.
Vest4		0.062
MutPred		0.26		.;Gain of MoRF binding (P = 0.0653);.;Gain of MoRF binding (P = 0.0653);.;.;Gain of MoRF binding (P = 0.0653);.;.;
MVP		0.44
MPC		0.17
ClinPred		0.067	T
GERP RS		1.4
Varity_R		0.13
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-103340010;