22-30607082-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000402281.5(PES1):c.-991G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 591,184 control chromosomes in the GnomAD database, including 9,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1954 hom., cov: 30)
  • Exomes 𝑓: 0.17 (7628 hom.)
• Consequence: PES1 ENST00000402281.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00900

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]

TCN2 (HGNC:11653): (transcobalamin 2) This gene encodes a member of the vitamin B12-binding protein family. This family of proteins, alternatively referred to as R binders, is expressed in various tissues and secretions. This plasma protein binds cobalamin and mediates the transport of cobalamin into cells. This protein and other mammalian cobalamin-binding proteins, such as transcobalamin I and gastric intrisic factor, may have evolved by duplication of a common ancestral gene. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 22-30607082-C-T is Benign according to our data. Variant chr22-30607082-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 369375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PES1	ENST00000402281.5	c.-991G>A		5_prime_UTR_variant	1/17	2
TCN2	ENST00000423350.1	n.80C>T		non_coding_transcript_exon_variant	1/2	2
TCN2	ENST00000450638.5			upstream_gene_variant		3
PES1	ENST00000492986.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21627 AN: 152002 Hom.: 1954 Cov.: 30

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.150

GnomAD4 exome AF: 0.173 AC: 75877 AN: 439064 Hom.: 7628 Cov.: 5 AF XY: 0.169 AC XY: 38981 AN XY: 231174

Gnomad4 AFR exome AF: 0.0373

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.142 AC: 21629 AN: 152120 Hom.: 1954 Cov.: 30 AF XY: 0.137 AC XY: 10193 AN XY: 74384

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.153

Alfa AF: 0.189 Hom.: 4186

Bravo AF: 0.139

Asia WGS AF: 0.120 AC: 415 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 09, 2019

- -

Transcobalamin II deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	11
Dann	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs5753231; hg19: chr22-31003069;