4-2128131-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_181808.4(POLN):c.1964C>T(p.Ser655Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,362 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLN NM_181808.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLN	NM_181808.4	c.1964C>T	p.Ser655Phe	missense_variant	19/26	ENST00000511885.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLN	ENST00000511885.6	c.1964C>T	p.Ser655Phe	missense_variant	19/26	5	NM_181808.4	P1
POLN	ENST00000382865.5	c.1964C>T	p.Ser655Phe	missense_variant	17/24	1		P1
POLN	ENST00000511098.1	c.863C>T	p.Ser288Phe	missense_variant	12/19	1
POLN	ENST00000514858.5	n.971C>T		non_coding_transcript_exon_variant	10/14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450362 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 722342

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 26, 2022

The c.1964C>T (p.S655F) alteration is located in exon 17 (coding exon 17) of the POLN gene. This alteration results from a C to T substitution at nucleotide position 1964, causing the serine (S) at amino acid position 655 to be replaced by a phenylalanine (F). 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	0.15
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.55	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.93	P;P
Vest4		0.57
MutPred		0.68		Loss of disorder (P = 0.011);Loss of disorder (P = 0.011);
MVP		0.96
MPC		0.39
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.88
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: -18

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

Publications

LitVar

Other links and lift over

dbSNP: rs1209335735; hg19: chr4-2129858;