dbSNP rs767673605: RPL21:p.Arg108His (chr13-27256264-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000982.4(RPL21):c.323G>A(p.Arg108His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,435,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

RPL21
NM_000982.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.78

Publications

0 publications found

Variant links:

Genes affected

RPL21 (HGNC:10313): (ribosomal protein L21) 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 ribosomal protein that is a component of the 60S subunit. The protein belongs to the L21E family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

RPL21 Gene-Disease associations (from GenCC):

hypotrichosis 12
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypotrichosis simplex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RPL21 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL21	NM_000982.4 link	c.323G>A	p.Arg108His	missense_variant	Exon 5 of 6	ENST00000311549.11	NP_000973.2	P46778Q6IAX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL21	ENST00000311549.11 link	c.323G>A	p.Arg108His	missense_variant	Exon 5 of 6	1	NM_000982.4	ENSP00000346027.4		P46778

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000488

AC:

AN:

1435660

Hom.:

Cov.:

AF XY:

0.00000560

AC XY:

AN XY:

714782

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32482

American (AMR)

AF:

0.0000227

AC:

AN:

44132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25896

East Asian (EAS)

AF:

0.00

AC:

AN:

39098

South Asian (SAS)

AF:

0.00

AC:

AN:

84542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5138

European-Non Finnish (NFE)

AF:

0.00000458

AC:

AN:

1091980

Other (OTH)

AF:

0.0000168

AC:

AN:

59374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.323G>A (p.R108H) alteration is located in exon 5 (coding exon 4) of the RPL21 gene. This alteration results from a G to A substitution at nucleotide position 323, causing the arginine (R) at amino acid position 108 to be replaced by a histidine (H). 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

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T;T;T;.

Eigen

Benign

-0.017

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.54

.;.;.;T;T

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.59

D;D;D;D;D

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.1

L;L;L;L;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.6

D;D;D;D;.

REVEL

Uncertain

0.46

Sift

Benign

0.069

T;T;T;T;.

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

0.0080

B;B;B;B;.

Vest4

0.79

MutPred

0.48

Loss of MoRF binding (P = 0.0652);Loss of MoRF binding (P = 0.0652);Loss of MoRF binding (P = 0.0652);Loss of MoRF binding (P = 0.0652);Loss of MoRF binding (P = 0.0652);

MVP

0.96

MPC

1.3

ClinPred

0.98

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.74

Mutation Taster

=28/72

disease causing

(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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rs767673605

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over