22-30581091-G-A

Position:

• chr22-30581091-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000354694.12(PES1):​c.833C>T​(p.Ala278Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PES1 ENST00000354694.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4149447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PES1	NM_014303.4	c.833C>T	p.Ala278Val	missense_variant	9/15	ENST00000354694.12	NP_055118.1
PES1	NM_001243225.2	c.833C>T	p.Ala278Val	missense_variant	9/15		NP_001230154.1
PES1	NM_001282327.1	c.416C>T	p.Ala139Val	missense_variant	11/17		NP_001269256.1
PES1	NM_001282328.1	c.416C>T	p.Ala139Val	missense_variant	11/17		NP_001269257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PES1	ENST00000354694.12	c.833C>T	p.Ala278Val	missense_variant	9/15	1	NM_014303.4	ENSP00000346725	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455348 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723860

Gnomad4 AFR exome AF: 0.00

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

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

Apr 24, 2024

The c.833C>T (p.A278V) alteration is located in exon 9 (coding exon 9) of the PES1 gene. This alteration results from a C to T substitution at nucleotide position 833, causing the alanine (A) at amino acid position 278 to be replaced by a valine (V). 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	0.40
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;.;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Pathogenic	3.1	M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.45
MutPred		0.52		Gain of helix (P = 0.0425);.;.;.;Gain of helix (P = 0.0425);
MVP		0.48
MPC		0.38
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-30977078;