11-65125520-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_004927.4(MRPL49):​c.262C>T​(p.Arg88Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,940 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R88H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

MRPL49
NM_004927.4 missense

Scores

7
10
2

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 7.18
Variant links:
Genes affected
MRPL49 (HGNC:1176): (mitochondrial ribosomal protein L49) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. Pseudogenes corresponding to this gene are found on chromosomes 5q and 8p. [provided by RefSeq, May 2011]
SYVN1 (HGNC:20738): (synoviolin 1) This gene encodes a protein involved in endoplasmic reticulum (ER)-associated degradation. The encoded protein removes unfolded proteins, accumulated during ER stress, by retrograde transport to the cytosol from the ER. This protein also uses the ubiquitin-proteasome system for additional degradation of unfolded proteins. Sequence analysis identified two transcript variants that encode different isoforms. [provided by RefSeq, May 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-65125521-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2691724.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 11-65125520-C-T is Pathogenic according to our data. Variant chr11-65125520-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2691723.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MRPL49NM_004927.4 linkc.262C>T p.Arg88Cys missense_variant Exon 3 of 4 ENST00000279242.7 NP_004918.1 Q13405A0A024R578
MRPL49NR_037567.1 linkn.342C>T non_coding_transcript_exon_variant Exon 3 of 4
MRPL49NR_037568.2 linkn.137C>T non_coding_transcript_exon_variant Exon 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MRPL49ENST00000279242.7 linkc.262C>T p.Arg88Cys missense_variant Exon 3 of 4 1 NM_004927.4 ENSP00000279242.2 Q13405

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152106
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251392
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135874
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461834
Hom.:
0
Cov.:
31
AF XY:
0.0000289
AC XY:
21
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000387
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152106
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Perrault syndrome 1 Pathogenic:1
Jan 31, 2024
Newman Lab, University of Manchester
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 60 Pathogenic:1
May 13, 2025
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T;D
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
D;T
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
-0.17
T
MutationAssessor
Uncertain
2.3
.;M
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-8.0
D;D
REVEL
Pathogenic
0.70
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.045
D;T
Polyphen
0.96
.;D
Vest4
0.99
MutPred
0.95
Loss of MoRF binding (P = 0.0106);Loss of MoRF binding (P = 0.0106);
MVP
0.93
MPC
0.68
ClinPred
0.69
D
GERP RS
5.9
Varity_R
0.72
gMVP
0.92

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: rs758327244; hg19: chr11-64892992; API