4-2085677-A-T

Variant names:

• chr4-2085677-A-T
• rs34554757
• NM_181808.4:c.2133T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_181808.4(POLN):​c.2133T>A​(p.Phe711Leu) 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 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLN NM_181808.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 5 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]

ENSG00000290263 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

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.2133T>A	p.Phe711Leu	missense	Exon 21 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.2133T>A	p.Phe711Leu	missense	Exon 21 of 26	ENSP00000435506.1	Q7Z5Q5-1
	POLN	ENST00000382865.5	TSL:1	c.2133T>A	p.Phe711Leu	missense	Exon 19 of 24	ENSP00000372316.1	Q7Z5Q5-1
	POLN	ENST00000511098.1	TSL:1	c.1029T>A	p.Phe343Leu	missense	Exon 14 of 19	ENSP00000426401.1	H0YA88

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727192

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.77	P
Vest4		0.77
MutPred		0.40		Loss of methylation at K716 (P = 0.0858)
MVP		0.90
MPC		0.45
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.89
gMVP		0.76
Mutation Taster		=96/4	polymorphism

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: rs34554757; hg19: chr4-2087404;