NM_014303.4:c.1385A>G

Variant names:

• chr22-30579273-T-C
• NM_014303.4:c.1385A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014303.4(PES1):​c.1385A>G​(p.Glu462Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,449,066 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: PES1 NM_014303.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07683286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PES1	NM_014303.4	c.1385A>G	p.Glu462Gly	missense_variant	Exon 13 of 15	ENST00000354694.12	NP_055118.1
PES1	NM_001243225.2	c.1370A>G	p.Glu457Gly	missense_variant	Exon 13 of 15		NP_001230154.1
PES1	NM_001282327.1	c.968A>G	p.Glu323Gly	missense_variant	Exon 15 of 17		NP_001269256.1
PES1	NM_001282328.1	c.968A>G	p.Glu323Gly	missense_variant	Exon 15 of 17		NP_001269257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PES1	ENST00000354694.12	c.1385A>G	p.Glu462Gly	missense_variant	Exon 13 of 15	1	NM_014303.4	ENSP00000346725.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000828 AC: 12 AN: 1449066 Hom.: 0 Cov.: 32 AF XY: 0.00000554 AC XY: 4 AN XY: 721420

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1385A>G (p.E462G) alteration is located in exon 13 (coding exon 13) of the PES1 gene. This alteration results from a A to G substitution at nucleotide position 1385, causing the glutamic acid (E) at amino acid position 462 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	0.079
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.63	T;.;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.077	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D
REVEL	Benign	0.051
Sift	Benign	0.098	T;T;T;T;T
Sift4G	Uncertain	0.058	T;T;T;T;T
Polyphen		0.018	B;.;.;B;B
Vest4		0.24
MutPred		0.24		Loss of helix (P = 0.0237);.;.;.;.;
MVP		0.27
MPC		0.75
ClinPred		0.34	T
GERP RS		3.1
Varity_R		0.094
gMVP		0.30

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: chr22-30975260;