22-30581027-C-G

Variant summary

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

The NM_014303.4(PES1):c.897G>C(p.Glu299Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,612,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: PES1 NM_014303.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.460

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=0.032566905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PES1	NM_014303.4	c.897G>C	p.Glu299Asp	missense_variant	9/15	ENST00000354694.12
PES1	NM_001243225.2	c.897G>C	p.Glu299Asp	missense_variant	9/15
PES1	NM_001282327.1	c.480G>C	p.Glu160Asp	missense_variant	11/17
PES1	NM_001282328.1	c.480G>C	p.Glu160Asp	missense_variant	11/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PES1	ENST00000354694.12	c.897G>C	p.Glu299Asp	missense_variant	9/15	1	NM_014303.4	P3

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000705

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000479 AC: 119 AN: 248476 Hom.: 0 AF XY: 0.000482 AC XY: 65 AN XY: 134904

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000814

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000505 AC: 737 AN: 1460250 Hom.: 0 Cov.: 32 AF XY: 0.000496 AC XY: 360 AN XY: 726428

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000571

Gnomad4 NFE exome AF: 0.000615

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74496

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000381 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000495 AC: 60

EpiCase AF: 0.00109

EpiControl AF: 0.00113

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

Jun 11, 2021

The c.897G>C (p.E299D) alteration is located in exon 9 (coding exon 9) of the PES1 gene. This alteration results from a G to C substitution at nucleotide position 897, causing the glutamic acid (E) at amino acid position 299 to be replaced by an aspartic acid (D). 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	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	10
Dann	Benign	0.96
DEOGEN2	Uncertain	0.44	T;.;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.77	T;.;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.033	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;.;.;M
MutationTaster	Benign	0.90	D;D;D;D;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.031	B;.;.;B;B
Vest4		0.32
MutPred		0.19		Loss of helix (P = 0.1299);.;.;.;Loss of helix (P = 0.1299);
MVP		0.30
MPC		0.32
ClinPred		0.012	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2108110; hg19: chr22-30977014;