17-42998817-G-A

Variant names:

• chr17-42998817-G-A
• rs749989076
• NM_000988.5:c.67G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000988.5(RPL27):​c.67G>A​(p.Ala23Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A23S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPL27 NM_000988.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.67
• Publications: 0 publications found

Genes affected

RPL27 (HGNC:10328): (ribosomal protein L27) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four RNA species and approximately 80 structurally distinct proteins. This gene encodes a member of the L27e family of ribosomal proteins and a component of the 60S subunit. A splice site mutation in this gene has been identified in a Diamond-Blackfan anemia (DBA) patient. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Mar 2017]

RPL27 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 16

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

LOC124904006 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000988.5. 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
	RPL27	NM_000988.5	MANE Select	c.67G>A	p.Ala23Thr	missense	Exon 2 of 5	NP_000979.1	P61353
	RPL27	NM_001349921.2		c.67G>A	p.Ala23Thr	missense	Exon 2 of 5	NP_001336850.1	P61353
	RPL27	NM_001349922.2		c.67G>A	p.Ala23Thr	missense	Exon 1 of 4	NP_001336851.1	P61353

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL27	ENST00000253788.12	TSL:1 MANE Select	c.67G>A	p.Ala23Thr	missense	Exon 2 of 5	ENSP00000253788.5	P61353
	RPL27	ENST00000589913.6	TSL:1	c.67G>A	p.Ala23Thr	missense	Exon 1 of 4	ENSP00000464813.1	P61353
	RPL27	ENST00000911442.1		c.67G>A	p.Ala23Thr	missense	Exon 2 of 6	ENSP00000581501.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251226 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461614 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44710

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111858

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.97	D
Vest4		0.95
MutPred		0.72		Gain of phosphorylation at A23 (P = 0.0537)
MVP		0.62
MPC		0.76
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.68
gMVP		0.85
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs749989076; hg19: chr17-41150834;