chr2-55234121-A-G

Variant names:

• chr2-55234121-A-G
• NM_002954.6:c.106A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002954.6(RPS27A):​c.106A>G​(p.Ile36Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,640 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPS27A NM_002954.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27
• Publications: 0 publications found

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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002954.6. 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
	RPS27A	NM_002954.6	MANE Select	c.106A>G	p.Ile36Val	missense splice_region	Exon 4 of 6	NP_002945.1	B2RDW1
	RPS27A	NM_001135592.2		c.106A>G	p.Ile36Val	missense splice_region	Exon 4 of 6	NP_001129064.1	B2RDW1
	RPS27A	NM_001177413.1		c.106A>G	p.Ile36Val	missense splice_region	Exon 3 of 5	NP_001170884.1	B2RDW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS27A	ENST00000272317.11	TSL:1 MANE Select	c.106A>G	p.Ile36Val	missense splice_region	Exon 4 of 6	ENSP00000272317.6	P62979
	RPS27A	ENST00000404735.1	TSL:1	c.106A>G	p.Ile36Val	missense splice_region	Exon 3 of 5	ENSP00000385659.1	P62979
	RPS27A	ENST00000859841.1		c.106A>G	p.Ile36Val	missense splice_region	Exon 4 of 6	ENSP00000529900.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460640 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726710

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110902

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.034
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.34
Sift	Benign	0.074	T
Sift4G	Benign	0.071	T
Polyphen		0.010	B
Vest4		0.51
MutPred		0.62		Loss of catalytic residue at P38 (P = 0.0536)
MVP		0.68
MPC		0.65
ClinPred		0.90	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.41
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr2-55461257;