NM_175854.8:c.331C>T

Variant names:

• chr13-28138988-C-T
• rs758205133
• NM_175854.8:c.331C>T

Variant summary

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

The NM_175854.8(PAN3):​c.331C>T​(p.Pro111Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000717 in 1,115,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: PAN3 NM_175854.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.370

Genes affected

PAN3 (HGNC:29991): (poly(A) specific ribonuclease subunit PAN3) Contributes to poly(A)-specific ribonuclease activity. Predicted to be involved in nuclear-transcribed mRNA poly(A) tail shortening. Predicted to act upstream of or within deadenylation-dependent decapping of nuclear-transcribed mRNA; positive regulation of cytoplasmic mRNA processing body assembly; and protein targeting. Part of PAN complex. [provided by Alliance of Genome Resources, Apr 2022]

PAN3-AS1 (HGNC:39932): (PAN3 antisense RNA 1)

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=0.17953506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAN3	NM_175854.8	c.331C>T	p.Pro111Ser	missense_variant	Exon 1 of 19	ENST00000380958.8	NP_787050.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAN3	ENST00000380958.8	c.331C>T	p.Pro111Ser	missense_variant	Exon 1 of 19	5	NM_175854.8	ENSP00000370345.3
PAN3	ENST00000503791.5	n.483C>T		non_coding_transcript_exon_variant	Exon 1 of 14	2
PAN3	ENST00000399613.1	c.-108C>T		upstream_gene_variant		5		ENSP00000382522.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000717 AC: 8 AN: 1115866 Hom.: 0 Cov.: 32 AF XY: 0.0000113 AC XY: 6 AN XY: 532538

Gnomad4 AFR exome AF: 0.000130

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000532

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ExAC AF: 0.0000143 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331C>T (p.P111S) alteration is located in exon 1 (coding exon 1) of the PAN3 gene. This alteration results from a C to T substitution at nucleotide position 331, causing the proline (P) at amino acid position 111 to be replaced by a serine (S). 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	0.085
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.021
Sift	Benign	0.15	T
Sift4G	Benign	0.60	T
Vest4		0.14
MutPred		0.18		Gain of phosphorylation at P111 (P = 0.0101);
MVP		0.25
MPC		0.46
ClinPred		0.48	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs758205133; hg19: chr13-28713125;