16-1947041-C-T

Variant names:

• chr16-1947041-C-T
• rs149043671
• NM_005061.3:c.746G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL3L	NM_005061.3	c.746G>A	p.Arg249His	missense_variant	Exon 6 of 10	ENST00000268661.8	NP_005052.1
RPL3L	XM_011522571.3	c.761G>A	p.Arg254His	missense_variant	Exon 6 of 10		XP_011520873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL3L	ENST00000268661.8	c.746G>A	p.Arg249His	missense_variant	Exon 6 of 10	1	NM_005061.3	ENSP00000268661.7

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152246 Hom.: 0 Cov.: 34

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

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 249990 AF XY: 0.0000664

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 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

Gnomad4 AFR exome AF: 0.000777 AC: 26 AN: 33466

Gnomad4 AMR exome AF: 0.0000448 AC: 2 AN: 44666

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26112

Gnomad4 EAS exome AF: 0.0000756 AC: 3 AN: 39696

Gnomad4 SAS exome AF: 0.000139 AC: 12 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52582

Gnomad4 NFE exome AF: 0.0000675 AC: 75 AN: 1111908

Gnomad4 Remaining exome AF: 0.000215 AC: 13 AN: 60360

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152364 Hom.: 0 Cov.: 34 AF XY: 0.000255 AC XY: 19 AN XY: 74512

Gnomad4 AFR AF: 0.000697 AC: 0.00069735 AN: 0.00069735

Gnomad4 AMR AF: 0.000131 AC: 0.000130599 AN: 0.000130599

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000206954 AN: 0.000206954

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000103 AC: 0.000102899 AN: 0.000102899

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000104 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

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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
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
Mutation Taster		=63/37	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

LitVar

Other links and lift over

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