chr22-30579762-C-T

Position:

• chr22-30579762-C-T

Variant summary

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

The ENST00000354694.12(PES1):​c.1343G>A​(p.Gly448Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PES1 ENST00000354694.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PES1	NM_014303.4	c.1343G>A	p.Gly448Glu	missense_variant	12/15	ENST00000354694.12	NP_055118.1
PES1	NM_001243225.2	c.1328G>A	p.Gly443Glu	missense_variant	12/15		NP_001230154.1
PES1	NM_001282327.1	c.926G>A	p.Gly309Glu	missense_variant	14/17		NP_001269256.1
PES1	NM_001282328.1	c.926G>A	p.Gly309Glu	missense_variant	14/17		NP_001269257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PES1	ENST00000354694.12	c.1343G>A	p.Gly448Glu	missense_variant	12/15	1	NM_014303.4	ENSP00000346725	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

May 17, 2023

The c.1343G>A (p.G448E) alteration is located in exon 12 (coding exon 12) of the PES1 gene. This alteration results from a G to A substitution at nucleotide position 1343, causing the glycine (G) at amino acid position 448 to be replaced by a glutamic acid (E). 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	Uncertain	0.49
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.053	T;T;T;D;T
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		1.0	D;.;.;D;D
Vest4		0.71
MutPred		0.15		Gain of helix (P = 0.027);.;.;.;.;
MVP		0.33
MPC		1.0
ClinPred		0.95	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.52

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: rs1035694104; hg19: chr22-30975749; COSMIC: COSV58828561; COSMIC: COSV58828561;