9-4826926-C-G

Variant names:

• chr9-4826926-C-G
• rs1460301381
• NM_005772.5:c.277C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005772.5(RCL1):​c.277C>G​(p.Arg93Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,798 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. R93C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RCL1 NM_005772.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.49
• Publications: 1 publications found

Genes affected

RCL1 (HGNC:17687): (RNA terminal phosphate cyclase like 1) Predicted to enable endoribonuclease activity. Predicted to be involved in endonucleolytic cleavage of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Predicted to act upstream of or within endonucleolytic cleavage in 5'-ETS of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) and endonucleolytic cleavage in ITS1 to separate SSU-rRNA from 5.8S rRNA and LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Predicted to be located in nucleoplasm. Predicted to be active in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005772.5. 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
	RCL1	NM_005772.5	MANE Select	c.277C>G	p.Arg93Gly	missense	Exon 3 of 9	NP_005763.3
	RCL1	NM_001286699.2		c.-90-6228C>G		intron	N/A	NP_001273628.1	Q5VZU3
	RCL1	NM_001286700.2		c.-91+3307C>G		intron	N/A	NP_001273629.1	Q5VZU3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCL1	ENST00000381750.9	TSL:1 MANE Select	c.277C>G	p.Arg93Gly	missense	Exon 3 of 9	ENSP00000371169.4	Q9Y2P8-1
	RCL1	ENST00000381732.3	TSL:2	c.277C>G	p.Arg93Gly	missense	Exon 3 of 3	ENSP00000371151.3	Q5VYW8
	RCL1	ENST00000442869.5	TSL:3	c.-91+3307C>G		intron	N/A	ENSP00000412000.2	Q5VZU3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727196

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.0098	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.82		Loss of stability (P = 0.1052)
MVP		0.50
MPC		0.40
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.90
Mutation Taster		=2/98	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: rs1460301381; hg19: chr9-4826926;