2-55234273-T-C

Variant names:

• chr2-55234273-T-C
• rs74478570
• NM_002954.6:c.189+69T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002954.6(RPS27A):​c.189+69T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,147,760 control chromosomes in the GnomAD database, including 1,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (906 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (605 hom.)
• Consequence: RPS27A NM_002954.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.504

Genes affected

RPS27A (HGNC:10417): (ribosomal protein S27a) Ubiquitin, a highly conserved protein that has a major role in targeting cellular proteins for degradation by the 26S proteosome, is synthesized as a precursor protein consisting of either polyubiquitin chains or a single ubiquitin fused to an unrelated protein. This gene encodes a fusion protein consisting of ubiquitin at the N terminus and ribosomal protein S27a at the C terminus. When expressed in yeast, the protein is post-translationally processed, generating free ubiquitin monomer and ribosomal protein S27a. Ribosomal protein S27a is a component of the 40S subunit of the ribosome and belongs to the S27AE family of ribosomal proteins. It contains C4-type zinc finger domains and is located in the cytoplasm. Pseudogenes derived from this gene are present in the genome. As with ribosomal protein S27a, ribosomal protein L40 is also synthesized as a fusion protein with ubiquitin; similarly, ribosomal protein S30 is synthesized as a fusion protein with the ubiquitin-like protein fubi. Multiple alternatively spliced transcript variants that encode the same proteins have been identified.[provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018050075).
• BP6: Variant 2-55234273-T-C is Benign according to our data. Variant chr2-55234273-T-C is described in ClinVar as [Benign]. Clinvar id is 1242743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS27A	NM_002954.6	c.189+69T>C		intron_variant	Intron 4 of 5	ENST00000272317.11	NP_002945.1
RPS27A	NM_001135592.2	c.189+69T>C		intron_variant	Intron 4 of 5		NP_001129064.1
RPS27A	NM_001177413.1	c.189+69T>C		intron_variant	Intron 3 of 4		NP_001170884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS27A	ENST00000272317.11	c.189+69T>C		intron_variant	Intron 4 of 5	1	NM_002954.6	ENSP00000272317.6

Frequencies

GnomAD3 genomes AF: 0.0608 AC: 9242 AN: 152126 Hom.: 908 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.0435

GnomAD4 exome AF: 0.00782 AC: 7786 AN: 995518 Hom.: 605 Cov.: 13 AF XY: 0.00681 AC XY: 3502 AN XY: 513984

Gnomad4 AFR exome AF: 0.210 AC: 4918 AN: 23452

Gnomad4 AMR exome AF: 0.0147 AC: 611 AN: 41546

Gnomad4 ASJ exome AF: 0.0224 AC: 517 AN: 23106

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 35644

Gnomad4 SAS exome AF: 0.000254 AC: 19 AN: 74852

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51468

Gnomad4 NFE exome AF: 0.00121 AC: 840 AN: 696528

Gnomad4 Remaining exome AF: 0.0187 AC: 834 AN: 44624

GnomAD4 genome AF: 0.0607 AC: 9247 AN: 152242 Hom.: 906 Cov.: 32 AF XY: 0.0582 AC XY: 4334 AN XY: 74426

Gnomad4 AFR AF: 0.204 AC: 0.204182 AN: 0.204182

Gnomad4 AMR AF: 0.0316 AC: 0.031634 AN: 0.031634

Gnomad4 ASJ AF: 0.0211 AC: 0.0210739 AN: 0.0210739

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000622 AC: 0.000622148 AN: 0.000622148

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00166 AC: 0.00166113 AN: 0.00166113

Gnomad4 OTH AF: 0.0431 AC: 0.0430871 AN: 0.0430871

Alfa AF: 0.0388 Hom.: 86

Bravo AF: 0.0711

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 16, 2021

GeneDx

Significance: 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	-0.82
CADD	Benign	4.9
DANN	Benign	0.85
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0018	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs74478570; hg19: chr2-55461409;