NM_005061.3:c.922G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_005061.3(RPL3L):c.922G>A(p.Asp308Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,666 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D308V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RPL3L
NM_005061.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 7.75

Publications

5 publications found

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]

RPL3L Gene-Disease associations (from GenCC):

cardiomyopathy, dilated, 2D
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
dilated cardiomyopathy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

RPL3L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-1946653-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1162248.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL3L	NM_005061.3 link	c.922G>A	p.Asp308Asn	missense_variant	Exon 7 of 10	ENST00000268661.8	NP_005052.1	Q92901
RPL3L	XM_011522571.3 link	c.937G>A	p.Asp313Asn	missense_variant	Exon 7 of 10		XP_011520873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL3L	ENST00000268661.8 link	c.922G>A	p.Asp308Asn	missense_variant	Exon 7 of 10	1	NM_005061.3	ENSP00000268661.7		Q92901

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460400

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111868

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.0000131

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000330

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy, dilated, 2D

Pathogenic:1

Jun 06, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

Jun 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RPL3L c.922G>A (p.Asp308Asn) results in a conservative amino acid change to a conserved residue located in the large globular domain on the cytoplasmic face of the encoded protein sequence (Ganapathi_2020). Another missense variant affecting this residue has been classified as pathogenic by OMIM (ClinVar). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249816 control chromosomes (gnomAD). c.922G>A has been reported in the literature in an individual affected with neonatal dilated cardiomyopathy (Ganapathi_2020), and the individual was reported with another missense variant in trans that was classified as pathogenic by OMIM. These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. One classified it as pathogenic one as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Jan 28, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 35323613, 36291431, 32514796) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.15

MutationAssessor

Pathogenic

3.0

PhyloP100

7.8

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.85

MutPred

0.90

Gain of glycosylation at T305 (P = 0.0596);

MVP

0.85

MPC

0.43

ClinPred

1.0

GERP RS

4.5

Varity_R

0.72

gMVP

0.81

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over