chr22-30579175-G-A

Variant names:

• chr22-30579175-G-A
• rs139112920
• NM_014303.4:c.1483C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014303.4(PES1):​c.1483C>T​(p.Arg495Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,608,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R495G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: PES1 NM_014303.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.404
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15234303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PES1	NM_014303.4	c.1483C>T	p.Arg495Trp	missense_variant	Exon 13 of 15	ENST00000354694.12	NP_055118.1
PES1	NM_001243225.2	c.1468C>T	p.Arg490Trp	missense_variant	Exon 13 of 15		NP_001230154.1
PES1	NM_001282327.1	c.1066C>T	p.Arg356Trp	missense_variant	Exon 15 of 17		NP_001269256.1
PES1	NM_001282328.1	c.1066C>T	p.Arg356Trp	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.1483C>T	p.Arg495Trp	missense_variant	Exon 13 of 15	1	NM_014303.4	ENSP00000346725.6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.0000206 AC: 5 AN: 242298 AF XY: 0.0000152

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000275 AC: 40 AN: 1456086 Hom.: 0 Cov.: 33 AF XY: 0.0000235 AC XY: 17 AN XY: 724592

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.0000224 AC: 1 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111502

Other (OTH) AF: 0.0000332 AC: 2 AN: 60298

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74460

African (AFR) AF: 0.0000241 AC: 1 AN: 41538

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000295 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.71	T;.;T;T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;.;.;.;.
PhyloP100		0.40
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.6	D;N;N;D;D
REVEL	Benign	0.074
Sift	Uncertain	0.015	D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D
Polyphen		0.83	P;.;.;P;P
Vest4		0.21
MVP		0.15
MPC		0.81
ClinPred		0.25	T
GERP RS		2.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.064
gMVP		0.17
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs139112920; hg19: chr22-30975162; COSMIC: COSV104406657; COSMIC: COSV104406657;