16-1946958-G-A

Variant names:

• chr16-1946958-G-A
• rs144221138
• NM_005061.3:c.829C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005061.3(RPL3L):​c.829C>T​(p.Arg277Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,607,230 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: RPL3L NM_005061.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.94

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL3L	NM_005061.3	c.829C>T	p.Arg277Cys	missense_variant	Exon 6 of 10	ENST00000268661.8	NP_005052.1
RPL3L	XM_011522571.3	c.844C>T	p.Arg282Cys	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.829C>T	p.Arg277Cys	missense_variant	Exon 6 of 10	1	NM_005061.3	ENSP00000268661.7

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 50 AN: 152268 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000241

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000247 AC: 61 AN: 247116 Hom.: 0 AF XY: 0.000238 AC XY: 32 AN XY: 134238

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000885

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000386

Gnomad NFE exome AF: 0.000420

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000401 AC: 583 AN: 1454962 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 292 AN XY: 723504

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000907

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000428

Gnomad4 NFE exome AF: 0.000483

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152268 Hom.: 1 Cov.: 34 AF XY: 0.000282 AC XY: 21 AN XY: 74396

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000577 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000164

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.829C>T (p.R277C) alteration is located in exon 6 (coding exon 6) of the RPL3L gene. This alteration results from a C to T substitution at nucleotide position 829, causing the arginine (R) at amino acid position 277 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiomyopathy, dilated, 2D Uncertain:1

Apr 11, 2023

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Heterozygous variant NM_005061.3:c.829C>T in RPL3L gene was found on the WES data in female proband (46 y.o., Caucasian) with obstructive HCM. The c.829C>T has AF=0,0002468 in The Genome Aggregation Database (gnomAD) (Date of access: 10-04-2023). Clinvar does not contain an entry for this variant. In accordance with ACMG(2015) criteria this variant is classified as a variant with uncertain significance with the following criteria selected: PM2, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.80
MPC		0.20
ClinPred		0.61	D
GERP RS		4.9
Varity_R		0.68
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144221138; hg19: chr16-1996959;