22-30579758-C-A

Variant summary

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

The NM_014303.4(PES1):c.1347G>T(p.Glu449Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PES1 NM_014303.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.401

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=0.061395556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PES1	NM_014303.4	c.1347G>T	p.Glu449Asp	missense_variant	12/15	ENST00000354694.12
PES1	NM_001243225.2	c.1332G>T	p.Glu444Asp	missense_variant	12/15
PES1	NM_001282327.1	c.930G>T	p.Glu310Asp	missense_variant	14/17
PES1	NM_001282328.1	c.930G>T	p.Glu310Asp	missense_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PES1	ENST00000354694.12	c.1347G>T	p.Glu449Asp	missense_variant	12/15	1	NM_014303.4	P3

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000479 AC: 12 AN: 250686 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135558

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461532 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727068

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.0000895

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74482

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000713 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

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

Aug 17, 2021

The c.1347G>T (p.E449D) alteration is located in exon 12 (coding exon 12) of the PES1 gene. This alteration results from a G to T substitution at nucleotide position 1347, causing the glutamic acid (E) at amino acid position 449 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	0.16
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.78	T;.;T;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.061	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;.;.;.;.
MutationTaster	Benign	0.54	D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N;N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.022	B;.;.;B;B
Vest4		0.35
MutPred		0.12		Gain of helix (P = 0.132);.;.;.;.;
MVP		0.36
MPC		0.57
ClinPred		0.054	T
GERP RS		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.24

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: rs139824084; hg19: chr22-30975745;