2-55234121-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS27A	NM_002954.6	c.106A>G	p.Ile36Val	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000272317.11	NP_002945.1
RPS27A	NM_001135592.2	c.106A>G	p.Ile36Val	missense_variant, splice_region_variant	Exon 4 of 6		NP_001129064.1
RPS27A	NM_001177413.1	c.106A>G	p.Ile36Val	missense_variant, splice_region_variant	Exon 3 of 5		NP_001170884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS27A	ENST00000272317.11	c.106A>G	p.Ile36Val	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_002954.6	ENSP00000272317.6

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.106A>G (p.I36V) alteration is located in exon 4 (coding exon 3) of the RPS27A gene. This alteration results from a A to G substitution at nucleotide position 106, causing the isoleucine (I) at amino acid position 36 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T
Eigen	Benign	0.034
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;.;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	L;L;.;.;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.88	N;N;.;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.074	T;T;.;D;T
Sift4G	Benign	0.071	T;T;.;T;T
Polyphen		0.010	B;B;.;.;B
Vest4		0.51
MutPred		0.62		Loss of catalytic residue at P38 (P = 0.0536);Loss of catalytic residue at P38 (P = 0.0536);Loss of catalytic residue at P38 (P = 0.0536);Loss of catalytic residue at P38 (P = 0.0536);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-55461257;