chr21-46287125-T-TAAAAA

Variant names:

• chr21-46287125-T-TAAAAA
• rs58271568
• NM_001314025.2:c.210+8_210+12dupAAAAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000397701.9(YBEY):​c.210+2_210+3insAAAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,427,076 control chromosomes in the GnomAD database, including 2,261 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.094 (856 hom., cov: 0)
  • Exomes 𝑓: 0.15 (1405 hom.)
• Consequence: YBEY ENST00000397701.9 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.890
• Publications: 1 publications found

Genes affected

YBEY (HGNC:1299): (ybeY metalloendoribonuclease) This gene encodes a highly conserved metalloprotein. A similar protein in bacteria acts as an endoribonuclease, and is thought to function in ribosomal RNA maturation and ribosome assembly. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 21-46287125-T-TAAAAA is Benign according to our data. Variant chr21-46287125-T-TAAAAA is described in ClinVar as [Benign]. Clinvar id is 403076.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YBEY	NM_001314025.2	c.210+8_210+12dupAAAAA		intron_variant	Intron 2 of 4	ENST00000397701.9	NP_001300954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YBEY	ENST00000397701.9	c.210+2_210+3insAAAAA		splice_region_variant, intron_variant	Intron 2 of 4	2	NM_001314025.2	ENSP00000380813.4

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14006 AN: 149096 Hom.: 857 Cov.: 0

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.0760

Gnomad AMR AF: 0.0824

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.000975

Gnomad SAS AF: 0.0470

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.0875

GnomAD2 exomes AF: 0.136 AC: 18450 AN: 136068 AF XY: 0.136

Gnomad AFR exome AF: 0.0763

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.0713

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.147 AC: 187760 AN: 1277876 Hom.: 1405 Cov.: 31 AF XY: 0.145 AC XY: 91548 AN XY: 632296

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0556 AC: 1580 AN: 28396

American (AMR) AF: 0.133 AC: 3880 AN: 29214

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3142 AN: 21506

East Asian (EAS) AF: 0.0412 AC: 1409 AN: 34232

South Asian (SAS) AF: 0.0886 AC: 6260 AN: 70674

European-Finnish (FIN) AF: 0.153 AC: 6814 AN: 44438

Middle Eastern (MID) AF: 0.114 AC: 550 AN: 4810

European-Non Finnish (NFE) AF: 0.158 AC: 156780 AN: 992376

Other (OTH) AF: 0.141 AC: 7345 AN: 52230

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0939 AC: 14010 AN: 149200 Hom.: 856 Cov.: 0 AF XY: 0.0917 AC XY: 6658 AN XY: 72580

African (AFR) AF: 0.0273 AC: 1114 AN: 40778

American (AMR) AF: 0.0822 AC: 1232 AN: 14992

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 373 AN: 3438

East Asian (EAS) AF: 0.000978 AC: 5 AN: 5114

South Asian (SAS) AF: 0.0473 AC: 224 AN: 4738

European-Finnish (FIN) AF: 0.141 AC: 1350 AN: 9608

Middle Eastern (MID) AF: 0.101 AC: 29 AN: 288

European-Non Finnish (NFE) AF: 0.140 AC: 9435 AN: 67270

Other (OTH) AF: 0.0866 AC: 179 AN: 2066

Alfa AF: 0.0829 Hom.: 259

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs58271568; hg19: chr21-47707039; COSMIC: COSV52440816; COSMIC: COSV52440816;