chr3-139348224-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_020191.4(MRPS22):​c.404G>A​(p.Arg135Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,992 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MRPS22
NM_020191.4 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:2

Conservation

PhyloP100: 9.06

Publications

8 publications found
Variant links:
Genes affected
MRPS22 (HGNC:14508): (mitochondrial ribosomal protein S22) 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. This gene encodes a 28S subunit protein that does not seem to have a counterpart in prokaryotic and fungal-mitochondrial ribosomes. This gene lies telomeric of and is transcribed in the opposite direction from the forkhead box L2 gene. A pseudogene corresponding to this gene is found on chromosome Xq. [provided by RefSeq, Jul 2008]
MRPS22 Gene-Disease associations (from GenCC):
  • mitochondrial disease
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • hypotonia with lactic acidemia and hyperammonemia
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
  • 46 XX gonadal dysgenesis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • ovarian dysgenesis 7
    Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MRPS22NM_020191.4 linkc.404G>A p.Arg135Gln missense_variant Exon 3 of 8 ENST00000680020.1 NP_064576.1 P82650-1
MRPS22NM_001363893.1 linkc.401G>A p.Arg134Gln missense_variant Exon 3 of 8 NP_001350822.1
MRPS22NM_001363857.1 linkc.281G>A p.Arg94Gln missense_variant Exon 3 of 8 NP_001350786.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MRPS22ENST00000680020.1 linkc.404G>A p.Arg135Gln missense_variant Exon 3 of 8 NM_020191.4 ENSP00000505414.1 P82650-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152208
Hom.:
0
Cov.:
33
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461784
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727204
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53392
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000719
AC:
8
AN:
1111942
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152208
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74362
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41448
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68044
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Premature ovarian failure Uncertain:2
Apr 22, 2019
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

This variant was identified as homozygous in a female individual with hypergonadotropic hypogonadism. -

Mar 11, 2018
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:research

This variant was identified as homozygous in a female with primary ovarian insufficiency, with reduced bone age, small uterus, and ovaries that could not be visualized by pelvic ultrasound. Karyotype was 46,XX. The variant was not identified in control databases including gnomAD, nor a population-specific (Turkish) database of > 1000 exomes. -

Ovarian dysgenesis 7 Pathogenic:1
Sep 18, 2018
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
0.59
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.79
D;D;D;.;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.97
.;D;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Uncertain
2.3
M;M;.;.;.
PhyloP100
9.1
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-3.0
D;D;D;D;D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.011
D;D;D;D;D
Sift4G
Uncertain
0.014
D;D;D;D;D
Polyphen
1.0
D;D;D;.;D
Vest4
0.90
MutPred
0.70
Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);.;.;.;
MVP
0.90
MPC
1.1
ClinPred
0.98
D
GERP RS
4.1
Varity_R
0.25
gMVP
0.81
Mutation Taster
=68/32
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

Other links and lift over

dbSNP: rs774237195; hg19: chr3-139067066; COSMIC: COSV60350598; COSMIC: COSV60350598; API