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GeneBe

16-1947041-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005061.3(RPL3L):c.746G>A(p.Arg249His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R249C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

RPL3L
NM_005061.3 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86
Variant links:
Genes affected
RPL3L (HGNC:10351): (ribosomal protein L3 like) This gene encodes a protein that shares sequence similarity with ribosomal protein L3. The protein belongs to the L3P family of ribosomal proteins. Unlike the ubiquitous expression of ribosomal protein genes, this gene has a tissue-specific pattern of expression, with the highest levels of expression in skeletal muscle and heart. It is not currently known whether the encoded protein is a functional ribosomal protein or whether it has evolved a function that is independent of the ribosome. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPL3LNM_005061.3 linkuse as main transcriptc.746G>A p.Arg249His missense_variant 6/10 ENST00000268661.8
RPL3LXM_011522571.3 linkuse as main transcriptc.761G>A p.Arg254His missense_variant 6/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPL3LENST00000268661.8 linkuse as main transcriptc.746G>A p.Arg249His missense_variant 6/101 NM_005061.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000256
AC:
39
AN:
152246
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000699
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000116
AC:
29
AN:
249990
Hom.:
0
AF XY:
0.0000664
AC XY:
9
AN XY:
135488
show subpopulations
Gnomad AFR exome
AF:
0.000992
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000443
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000897
AC:
131
AN:
1460764
Hom.:
0
Cov.:
33
AF XY:
0.0000839
AC XY:
61
AN XY:
726740
show subpopulations
Gnomad4 AFR exome
AF:
0.000777
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000675
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.000256
AC:
39
AN:
152364
Hom.:
0
Cov.:
34
AF XY:
0.000255
AC XY:
19
AN XY:
74512
show subpopulations
Gnomad4 AFR
AF:
0.000697
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000940
Hom.:
0
Bravo
AF:
0.000234
ESP6500AA
AF:
0.000682
AC:
3
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000132
AC:
16
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 12, 2023The c.746G>A (p.R249H) alteration is located in exon 6 (coding exon 6) of the RPL3L gene. This alteration results from a G to A substitution at nucleotide position 746, causing the arginine (R) at amino acid position 249 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
0.83
BayesDel_addAF
Uncertain
0.056
T
BayesDel_noAF
Pathogenic
0.25
Cadd
Uncertain
24
Dann
Uncertain
1.0
DEOGEN2
Benign
0.42
T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.86
D
M_CAP
Benign
0.044
D
MetaRNN
Uncertain
0.66
D
MetaSVM
Uncertain
0.11
D
MutationAssessor
Pathogenic
3.6
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-4.6
D
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.041
D
Polyphen
1.0
D
Vest4
0.97
MVP
0.83
MPC
0.16
ClinPred
0.30
T
GERP RS
4.0
Varity_R
0.85
gMVP
0.88

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149043671; hg19: chr16-1997042; COSMIC: COSV51907205; COSMIC: COSV51907205; API