chr22-30581014-C-A

Variant names:

• chr22-30581014-C-A
• rs144358121
• NM_014303.4:c.910G>T

Variant summary

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

The NM_014303.4(PES1):​c.910G>T​(p.Gly304Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,459,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. G304R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PES1 NM_014303.4 missense, splice_region
• Scores: Splicing: ADA: 0.8845
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.37
• Publications: 0 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PES1	NM_014303.4	c.910G>T	p.Gly304Trp	missense_variant, splice_region_variant	Exon 9 of 15	ENST00000354694.12	NP_055118.1
PES1	NM_001243225.2	c.910G>T	p.Gly304Trp	missense_variant, splice_region_variant	Exon 9 of 15		NP_001230154.1
PES1	NM_001282327.1	c.493G>T	p.Gly165Trp	missense_variant, splice_region_variant	Exon 11 of 17		NP_001269256.1
PES1	NM_001282328.1	c.493G>T	p.Gly165Trp	missense_variant, splice_region_variant	Exon 11 of 17		NP_001269257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PES1	ENST00000354694.12	c.910G>T	p.Gly304Trp	missense_variant, splice_region_variant	Exon 9 of 15	1	NM_014303.4	ENSP00000346725.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459736 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726248

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111070

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.;.;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;.;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M;.;.;.;M
PhyloP100		4.4
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.010	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.99	D;.;.;D;D
Vest4		0.60
MutPred		0.34		Gain of solvent accessibility (P = 0.0062);.;.;.;Gain of solvent accessibility (P = 0.0062);
MVP		0.36
MPC		0.84
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.14
gMVP		0.47
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Pathogenic	0.74
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: rs144358121; hg19: chr22-30977001; COSMIC: COSV100073269; COSMIC: COSV100073269;