22-30579175-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014303.4(PES1):c.1483C>G(p.Arg495Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,608,332 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: PES1 NM_014303.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.404

Genes affected

PES1 (HGNC:8848): (pescadillo ribosomal biogenesis factor 1) This gene encodes a nuclear protein that contains a breast cancer associated gene 1 (BRCA1) C-terminal interaction domain. The encoded protein interacts with BOP1 and WDR12 to form the PeBoW complex, which plays a critical role in cell proliferation via pre-rRNA processing and 60S ribosomal subunit maturation. Expression of this gene may play an important role in breast cancer proliferation and tumorigenicity. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Pseudogenes of this gene are located on the long arm of chromosome 4 and the short arm of chromosome 9. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02326253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PES1	NM_014303.4	c.1483C>G	p.Arg495Gly	missense_variant	13/15	ENST00000354694.12
PES1	NM_001243225.2	c.1468C>G	p.Arg490Gly	missense_variant	13/15
PES1	NM_001282327.1	c.1066C>G	p.Arg356Gly	missense_variant	15/17
PES1	NM_001282328.1	c.1066C>G	p.Arg356Gly	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PES1	ENST00000354694.12	c.1483C>G	p.Arg495Gly	missense_variant	13/15	1	NM_014303.4	P3

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000627 AC: 152 AN: 242298 Hom.: 0 AF XY: 0.000562 AC XY: 74 AN XY: 131612

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000489

Gnomad NFE exome AF: 0.000961

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.00114 AC: 1657 AN: 1456080 Hom.: 1 Cov.: 33 AF XY: 0.00106 AC XY: 768 AN XY: 724590

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000875

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000329

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74460

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.000752

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000527 AC: 64

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

Mar 29, 2022

The c.1483C>G (p.R495G) alteration is located in exon 13 (coding exon 13) of the PES1 gene. This alteration results from a C to G substitution at nucleotide position 1483, causing the arginine (R) at amino acid position 495 to be replaced by a glycine (G). 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	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.28	T;.;.;T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.73	T;.;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.023	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.70	N;N;N;N;N
REVEL	Benign	0.077
Sift	Benign	0.38	T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T
Polyphen		0.011	B;.;.;B;B
Vest4		0.15
MVP		0.26
MPC		0.79
ClinPred		0.018	T
GERP RS		2.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.061
gMVP		0.096

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: rs139112920; hg19: chr22-30975162; COSMIC: COSV99072323; COSMIC: COSV99072323;