chr19-48615417-G-C

Variant names:

• chr19-48615417-G-C
• rs755784683
• NM_000979.4:c.522C>G

Variant summary

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

The NM_000979.4(RPL18):​c.522C>G​(p.Phe174Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F174F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPL18 NM_000979.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.517
• Publications: 0 publications found

Genes affected

RPL18 (HGNC:10310): (ribosomal protein L18) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a member of the L18E family of ribosomal proteins that is a component of the 60S subunit. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

RPL18 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 18

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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, 0.848

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000979.4. 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
	RPL18	NM_000979.4	MANE Select	c.522C>G	p.Phe174Leu	missense	Exon 7 of 7	NP_000970.1	Q07020-1
	RPL18	NM_001270490.2		c.435C>G	p.Phe145Leu	missense	Exon 6 of 6	NP_001257419.1	Q07020-2
	RPL18	NR_073022.2		n.549C>G		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL18	ENST00000549920.6	TSL:1 MANE Select	c.522C>G	p.Phe174Leu	missense	Exon 7 of 7	ENSP00000447001.1	Q07020-1
	RPL18	ENST00000084795.9	TSL:1	c.525C>G	p.Phe175Leu	missense	Exon 6 of 6	ENSP00000084795.5	J3QQ67
	RPL18	ENST00000919794.1		c.513C>G	p.Phe171Leu	missense	Exon 7 of 7	ENSP00000589853.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.52
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.098	T
Polyphen		0.91	P
Vest4		0.79
MutPred		0.77		Loss of methylation at K170 (P = 0.1109)
MVP		0.58
MPC		1.2
ClinPred		1.0	D
GERP RS		-2.3
PromoterAI		0.075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.61
gMVP		0.54
Mutation Taster		=35/65	disease causing

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: rs755784683; hg19: chr19-49118674;