9-4841222-C-T

Variant names:

• chr9-4841222-C-T
• rs76643175
• ENST00000448872.6:c.17C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286701.2(RCL1):​c.17C>T​(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,613,850 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (56 hom.)
• Consequence: RCL1 NM_001286701.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58
• Publications: 0 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038719475).
• BP6: Variant 9-4841222-C-T is Benign according to our data. Variant chr9-4841222-C-T is described in ClinVar as Benign. ClinVar VariationId is 780781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286701.2. 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.585-10C>T		intron	N/A	NP_005763.3
	RCL1	NM_001286701.2		c.17C>T	p.Pro6Leu	missense	Exon 2 of 5	NP_001273630.1	Q9Y2P8-2
	RCL1	NM_001286699.2		c.111-10C>T		intron	N/A	NP_001273628.1	Q5VZU3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCL1	ENST00000448872.6	TSL:1	c.17C>T	p.Pro6Leu	missense	Exon 2 of 5	ENSP00000388096.2	Q9Y2P8-2
	RCL1	ENST00000381750.9	TSL:1 MANE Select	c.585-10C>T		intron	N/A	ENSP00000371169.4	Q9Y2P8-1
	RCL1	ENST00000381728.5	TSL:3	c.17C>T	p.Pro6Leu	missense	Exon 2 of 5	ENSP00000371147.1	Q9Y2P8-2

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2296 AN: 152030 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00390 AC: 979 AN: 250964 AF XY: 0.00288

Gnomad AFR exome AF: 0.0544

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00149 AC: 2173 AN: 1461702 Hom.: 56 Cov.: 30 AF XY: 0.00125 AC XY: 909 AN XY: 727164

African (AFR) AF: 0.0541 AC: 1809 AN: 33464

American (AMR) AF: 0.00311 AC: 139 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111882

Other (OTH) AF: 0.00303 AC: 183 AN: 60390

GnomAD4 genome AF: 0.0151 AC: 2298 AN: 152148 Hom.: 61 Cov.: 32 AF XY: 0.0142 AC XY: 1058 AN XY: 74384

African (AFR) AF: 0.0520 AC: 2154 AN: 41446

American (AMR) AF: 0.00752 AC: 115 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.0126 Hom.: 46

Bravo AF: 0.0180

ESP6500AA AF: 0.0488 AC: 215

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00480 AC: 583

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.7
DANN	Benign	0.76
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.6
PROVEAN	Benign	0.050	N
REVEL	Benign	0.050
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0090	D
Vest4		0.091
MVP		0.043
ClinPred		0.010	T
GERP RS		-10
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76643175; hg19: chr9-4841222;