chr21-25601452-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_017446.4(MRPL39):c.436T>A(p.Cys146Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000044 in 1,589,286 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: 32)
Exomes 𝑓: 0.0000042 ( 0 hom. )
Consequence
MRPL39
NM_017446.4 missense
NM_017446.4 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 5.92
Genes affected
MRPL39 (HGNC:14027): (mitochondrial ribosomal protein L39) 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 39S subunit protein. Two transcript variants encoding distinct isoforms have been described. A pseudogene corresponding to this gene is found on chromosome 5q. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.749
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRPL39 | NM_017446.4 | c.436T>A | p.Cys146Ser | missense_variant | 4/10 | ENST00000352957.9 | |
MRPL39 | NM_080794.4 | c.436T>A | p.Cys146Ser | missense_variant | 4/11 | ||
MRPL39 | XM_006724026.5 | c.436T>A | p.Cys146Ser | missense_variant | 4/10 | ||
MRPL39 | XM_011529651.3 | c.310T>A | p.Cys104Ser | missense_variant | 4/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRPL39 | ENST00000352957.9 | c.436T>A | p.Cys146Ser | missense_variant | 4/10 | 1 | NM_017446.4 | P1 | |
MRPL39 | ENST00000307301.11 | c.436T>A | p.Cys146Ser | missense_variant | 4/11 | 5 | |||
MRPL39 | ENST00000419219.1 | c.436T>A | p.Cys146Ser | missense_variant | 4/8 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000336 AC: 8AN: 238364Hom.: 0 AF XY: 0.0000465 AC XY: 6AN XY: 128950
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GnomAD4 exome AF: 0.00000417 AC: 6AN: 1437164Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1AN XY: 714208
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74324
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 06, 2024 | The c.436T>A (p.C146S) alteration is located in exon 4 (coding exon 4) of the MRPL39 gene. This alteration results from a T to A substitution at nucleotide position 436, causing the cysteine (C) at amino acid position 146 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;.
Vest4
MutPred
Gain of phosphorylation at C146 (P = 0.0714);Gain of phosphorylation at C146 (P = 0.0714);Gain of phosphorylation at C146 (P = 0.0714);
MVP
MPC
0.20
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at