Genetic Variant RRS1:p.Leu39Met (chr8-66429246-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.642

Publications

2 publications found

Variant links:

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 links:

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

RRS1-DT links:

LOC102724687 (HGNC:):

LOC102724687 links:

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ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015169.4. 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
	RRS1	NM_015169.4	MANE Select	c.115C>A	p.Leu39Met	missense	Exon 1 of 1	NP_055984.1	Q15050

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RRS1	ENST00000320270.4	TSL:6 MANE Select	c.115C>A	p.Leu39Met	missense	Exon 1 of 1	ENSP00000322396.2	Q15050
RRS1-DT	ENST00000659008.1		n.87+3038G>T		intron	N/A
RRS1-DT	ENST00000734543.1		n.116+3038G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

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:

AN:

226212

AF XY:

0.000146

show subpopulations

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.:

Cov.:

AF XY:

0.000187

AC XY:

135

AN XY:

721198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33338

American (AMR)

AF:

0.0000939

AC:

AN:

42580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25928

East Asian (EAS)

AF:

0.00

AC:

AN:

39154

South Asian (SAS)

AF:

0.00

AC:

AN:

85006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.000238

AC:

263

AN:

1107260

Other (OTH)

AF:

0.000334

AC:

AN:

59958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41448

American (AMR)

AF:

0.000131

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00298

Hom.:

Bravo

AF:

0.000189

ExAC

AF:

0.000215

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Uncertain

0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.094

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.58

MutationAssessor

Pathogenic

3.1

PhyloP100

0.64

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.48

Sift

Uncertain

0.026

Sift4G

Uncertain

0.047

Polyphen

1.0

Vest4

0.68

MutPred

0.85

Gain of sheet (P = 0.0827)

MVP

0.69

MPC

1.4

ClinPred

0.62

GERP RS

2.2

PromoterAI

0.0016

Neutral

(source)

Varity_R

0.67

gMVP

0.61

Mutation Taster

=66/34

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over