chr10-101580286-C-T

Variant names:

• chr10-101580286-C-T
• rs149081648
• NM_001174084.2:c.1325G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001174084.2(POLL):​c.1325G>A​(p.Gly442Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G442A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: POLL NM_001174084.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.52
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174084.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLL	NM_001174084.2	MANE Select	c.1325G>A	p.Gly442Asp	missense	Exon 8 of 9	NP_001167555.1	Q9UGP5-1
	POLL	NM_013274.4		c.1325G>A	p.Gly442Asp	missense	Exon 8 of 9	NP_037406.1	Q9UGP5-1
	POLL	NM_001174085.2		c.1049G>A	p.Gly350Asp	missense	Exon 8 of 9	NP_001167556.1	A8K860

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLL	ENST00000370162.8	TSL:1 MANE Select	c.1325G>A	p.Gly442Asp	missense	Exon 8 of 9	ENSP00000359181.3	Q9UGP5-1
	POLL	ENST00000299206.8	TSL:1	c.1325G>A	p.Gly442Asp	missense	Exon 8 of 9	ENSP00000299206.4	Q9UGP5-1
	POLL	ENST00000370169.5	TSL:1	c.1325G>A	p.Gly442Asp	missense	Exon 7 of 8	ENSP00000359188.1	Q9UGP5-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251196 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461658 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727134

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000138971), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.39
Sift	Benign	0.067	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.37		Loss of helix (P = 0.079)
MVP		0.69
MPC		0.77
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.81
Mutation Taster		=149/151	disease causing

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

Other links and lift over

dbSNP: rs149081648; hg19: chr10-103340043;