chr10-73250862-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016065.4(MRPS16):​c.404C>T​(p.Thr135Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MRPS16
NM_016065.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.150
Variant links:
Genes affected
MRPS16 (HGNC:14048): (mitochondrial ribosomal protein S16) 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 belongs to the ribosomal protein S16P family. The encoded protein is one of the most highly conserved ribosomal proteins between mammalian and yeast mitochondria. Three pseudogenes (located at 8q21.3, 20q13.32, 22q12-q13.1) for this gene have been described. [provided by RefSeq, Jul 2008]
DNAJC9-AS1 (HGNC:31432): (DNAJC9 and MRPS16 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.043988854).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MRPS16NM_016065.4 linkuse as main transcriptc.404C>T p.Thr135Ile missense_variant 3/3 ENST00000372945.8
DNAJC9-AS1NR_038373.1 linkuse as main transcriptn.175+2412G>A intron_variant, non_coding_transcript_variant
MRPS16XM_047425263.1 linkuse as main transcriptc.398C>T p.Thr133Ile missense_variant 3/3
MRPS16NM_001410935.1 linkuse as main transcriptc.274+901C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MRPS16ENST00000372945.8 linkuse as main transcriptc.404C>T p.Thr135Ile missense_variant 3/31 NM_016065.4 P1Q9Y3D3-1
DNAJC9-AS1ENST00000440197.2 linkuse as main transcriptn.182+2412G>A intron_variant, non_coding_transcript_variant 1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461652
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
727140
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 19, 2022Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with MRPS16-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 135 of the MRPS16 protein (p.Thr135Ile). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
14
DANN
Benign
0.95
DEOGEN2
Benign
0.0033
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.065
N
LIST_S2
Benign
0.45
T
M_CAP
Benign
0.0053
T
MetaRNN
Benign
0.044
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.59
N
REVEL
Benign
0.061
Sift
Uncertain
0.016
D
Sift4G
Uncertain
0.017
D
Polyphen
0.0
B
Vest4
0.041
MutPred
0.18
Loss of glycosylation at T135 (P = 0.0098);
MVP
0.14
MPC
0.18
ClinPred
0.069
T
GERP RS
-1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.17
gMVP
0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-75010620; API