rs116590536

Variant names:

• chr8-66429246-C-A
• rs116590536
• NM_015169.4:c.115C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-66429246-C-A
• chr8-66429246-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_015169.4(RRS1):​c.115C>A​(p.Leu39Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,603,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L39L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: RRS1 NM_015169.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.642

Genes affected

RRS1 (HGNC:17083): (ribosome biogenesis regulator 1 homolog) Enables 5S rRNA binding activity. Involved in several processes, including mitotic metaphase plate congression; protein localization to nucleolus; and ribosomal large subunit assembly. Located in condensed nuclear chromosome; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RRS1-DT (HGNC:50465): (RRS1 divergent transcript)

LOC102724687 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• BS2: High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRS1	NM_015169.4	c.115C>A	p.Leu39Met	missense_variant	Exon 1 of 1	ENST00000320270.4	NP_055984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRS1	ENST00000320270.4	c.115C>A	p.Leu39Met	missense_variant	Exon 1 of 1	6	NM_015169.4	ENSP00000322396.2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152178 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 26 AN: 226212 AF XY: 0.000146

Gnomad AFR exome AF: 0.000141

Gnomad AMR exome AF: 0.0000632

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000219

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000198 AC: 287 AN: 1451334 Hom.: 0 Cov.: 31 AF XY: 0.000187 AC XY: 135 AN XY: 721198

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.0000939 AC: 4 AN: 42580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39154

South Asian (SAS) AF: 0.00 AC: 0 AN: 85006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.000238 AC: 263 AN: 1107260

Other (OTH) AF: 0.000334 AC: 20 AN: 59958

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152178 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74334

African (AFR) AF: 0.0000965 AC: 4 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00298 Hom.: 1

Bravo AF: 0.000189

ExAC AF: 0.000215 AC: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115C>A (p.L39M) alteration is located in exon 1 (coding exon 1) of the RRS1 gene. This alteration results from a C to A substitution at nucleotide position 115, causing the leucine (L) at amino acid position 39 to be replaced by a methionine (M). 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	Benign	0.32
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.64
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.85		Gain of sheet (P = 0.0827);
MVP		0.69
MPC		1.4
ClinPred		0.62	D
GERP RS		2.2
PromoterAI		0.0016	Neutral
Varity_R		0.67
gMVP		0.61
Mutation Taster		=66/34	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

Publications

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Other links and lift over

dbSNP: rs116590536; hg19: chr8-67341481;