4-2073026-A-T

Variant names:

• chr4-2073026-A-T
• NM_181808.4:c.2459T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_181808.4(POLN):​c.2459T>A​(p.Leu820His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLN NM_181808.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65
• Publications: 0 publications found

Genes affected

POLN (HGNC:18870): (DNA polymerase nu) This gene encodes a DNA polymerase type-A family member. The encoded protein plays a role in DNA repair and homologous recombination. This gene shares its 5' exons with some transcripts from overlapping GeneID: 79441, which encodes an augmentin-like protein complex subunit. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181808.4. 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
	POLN	NM_181808.4	MANE Select	c.2459T>A	p.Leu820His	missense	Exon 25 of 26	NP_861524.2	Q7Z5Q5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLN	ENST00000511885.6	TSL:5 MANE Select	c.2459T>A	p.Leu820His	missense	Exon 25 of 26	ENSP00000435506.1	Q7Z5Q5-1
	POLN	ENST00000382865.5	TSL:1	c.2459T>A	p.Leu820His	missense	Exon 23 of 24	ENSP00000372316.1	Q7Z5Q5-1
	POLN	ENST00000511098.1	TSL:1	c.1355T>A	p.Leu452His	missense	Exon 18 of 19	ENSP00000426401.1	H0YA88

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461102 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726888

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52828

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111884

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.60		Gain of glycosylation at T824 (P = 0.035)
MVP		0.71
MPC		0.48
ClinPred		0.96	D
GERP RS		4.1
Varity_R		0.70
gMVP		0.45
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

hg19: chr4-2074753;