chr22-30607082-C-T

Variant names:

• chr22-30607082-C-T
• rs5753231
• ENST00000402281.5:c.-991G>A

Variant summary

Our verdict is Benign. The variant received -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:3
• 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.-250C>T		upstream_gene_variant		ENST00000215838.8	NP_000346.2
PES1	NM_001282327.1	c.-991G>A		upstream_gene_variant			NP_001269256.1
PES1	NM_001282328.1	c.-1038G>A		upstream_gene_variant			NP_001269257.1
TCN2	NM_001184726.2	c.-250C>T		upstream_gene_variant			NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.-250C>T		upstream_gene_variant		1	NM_000355.4	ENSP00000215838.3

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 AC: 464 AN: 12434

Gnomad4 AMR exome AF: 0.122 AC: 2329 AN: 19100

Gnomad4 ASJ exome AF: 0.243 AC: 3145 AN: 12926

Gnomad4 EAS exome AF: 0.129 AC: 3700 AN: 28646

Gnomad4 SAS exome AF: 0.102 AC: 4750 AN: 46466

Gnomad4 FIN exome AF: 0.127 AC: 3265 AN: 25642

Gnomad4 NFE exome AF: 0.201 AC: 53808 AN: 267370

Gnomad4 Remaining exome AF: 0.168 AC: 4139 AN: 24608

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 AC: 0.0407352 AN: 0.0407352

Gnomad4 AMR AF: 0.128 AC: 0.128156 AN: 0.128156

Gnomad4 ASJ AF: 0.251 AC: 0.251297 AN: 0.251297

Gnomad4 EAS AF: 0.141 AC: 0.140558 AN: 0.140558

Gnomad4 SAS AF: 0.105 AC: 0.104608 AN: 0.104608

Gnomad4 FIN AF: 0.130 AC: 0.130066 AN: 0.130066

Gnomad4 NFE AF: 0.207 AC: 0.20719 AN: 0.20719

Gnomad4 OTH AF: 0.153 AC: 0.153226 AN: 0.153226

Alfa AF: 0.181 Hom.: 5980

Bravo AF: 0.139

Asia WGS AF: 0.120 AC: 415 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Transcobalamin II deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.77
Mutation Taster		=300/0	polymorphism (auto)

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;