22-30580110-G-A

Variant names:

• chr22-30580110-G-A
• rs142191938
• NM_014303.4:c.1112C>T

Variant summary

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

The NM_014303.4(PES1):​c.1112C>T​(p.Ser371Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000626 in 1,614,004 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: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: PES1 NM_014303.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

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=0.05380377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PES1	NM_014303.4	c.1112C>T	p.Ser371Phe	missense_variant	Exon 11 of 15	ENST00000354694.12	NP_055118.1
PES1	NM_001243225.2	c.1097C>T	p.Ser366Phe	missense_variant	Exon 11 of 15		NP_001230154.1
PES1	NM_001282327.1	c.695C>T	p.Ser232Phe	missense_variant	Exon 13 of 17		NP_001269256.1
PES1	NM_001282328.1	c.695C>T	p.Ser232Phe	missense_variant	Exon 13 of 17		NP_001269257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PES1	ENST00000354694.12	c.1112C>T	p.Ser371Phe	missense_variant	Exon 11 of 15	1	NM_014303.4	ENSP00000346725.6

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000478

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251350 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135830

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461840 Hom.: 0 Cov.: 33 AF XY: 0.0000385 AC XY: 28 AN XY: 727224

Gnomad4 AFR exome AF: 0.00158

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74316

Gnomad4 AFR AF: 0.000917

Gnomad4 AMR AF: 0.00

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: 0.000478

Alfa AF: 0.000460 Hom.: 0

Bravo AF: 0.000348

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1112C>T (p.S371F) alteration is located in exon 11 (coding exon 11) of the PES1 gene. This alteration results from a C to T substitution at nucleotide position 1112, causing the serine (S) at amino acid position 371 to be replaced by a phenylalanine (F). 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	0.14
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.;T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;.;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.054	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;.;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.85	P;.;.;P;P
Vest4		0.23
MVP		0.25
MPC		0.61
ClinPred		0.22	T
GERP RS		4.3
Varity_R		0.41
gMVP		0.23

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: rs142191938; hg19: chr22-30976097;