chr22-30579235-C-T

Variant names:

• chr22-30579235-C-T
• rs1477313905
• NM_014303.4:c.1423G>A

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.1423G>A​(p.Gly475Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,452,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 0.0000048 (0 hom.)
• Consequence: PES1 NM_014303.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• Publications: 4 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=0.07958093).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014303.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PES1	NM_014303.4	MANE Select	c.1423G>A	p.Gly475Arg	missense	Exon 13 of 15	NP_055118.1	B2RDF2
	PES1	NM_001243225.2		c.1408G>A	p.Gly470Arg	missense	Exon 13 of 15	NP_001230154.1	O00541-2
	PES1	NM_001282327.1		c.1006G>A	p.Gly336Arg	missense	Exon 15 of 17	NP_001269256.1	F6VXF5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PES1	ENST00000354694.12	TSL:1 MANE Select	c.1423G>A	p.Gly475Arg	missense	Exon 13 of 15	ENSP00000346725.6	O00541-1
	PES1	ENST00000335214.8	TSL:1	c.1408G>A	p.Gly470Arg	missense	Exon 13 of 15	ENSP00000334612.6	O00541-2
	PES1	ENST00000898785.1		c.1426G>A	p.Gly476Arg	missense	Exon 13 of 15	ENSP00000568844.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000124 AC: 3 AN: 242760 AF XY: 0.00000757

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1452700 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 4 AN XY: 723168

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45422

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111034

Other (OTH) AF: 0.0000663 AC: 4 AN: 60294

GnomAD4 genome Cov.: 33

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.63
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.046
Sift	Benign	0.35	T
Sift4G	Benign	0.49	T
Polyphen		0.063	B
Vest4		0.13
MutPred		0.28		Loss of loop (P = 0.0203)
MVP		0.23
MPC		0.30
ClinPred		0.11	T
GERP RS		4.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.071
gMVP		0.15
Mutation Taster		=63/37	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: rs1477313905; hg19: chr22-30975222;