10-73250935-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016065.4(MRPS16):​c.331C>T​(p.Arg111Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,966 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R111R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

MRPS16
NM_016065.4 stop_gained

Scores

2
4
1

Clinical Significance

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

Conservation

PhyloP100: 1.78
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MRPS16NM_016065.4 linkuse as main transcriptc.331C>T p.Arg111Ter stop_gained 3/3 ENST00000372945.8
DNAJC9-AS1NR_038373.1 linkuse as main transcriptn.175+2485G>A intron_variant, non_coding_transcript_variant
MRPS16XM_047425263.1 linkuse as main transcriptc.325C>T p.Arg109Ter stop_gained 3/3
MRPS16NM_001410935.1 linkuse as main transcriptc.274+828C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MRPS16ENST00000372945.8 linkuse as main transcriptc.331C>T p.Arg111Ter stop_gained 3/31 NM_016065.4 P1Q9Y3D3-1
DNAJC9-AS1ENST00000440197.2 linkuse as main transcriptn.182+2485G>A intron_variant, non_coding_transcript_variant 1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152120
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251474
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461846
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152120
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74296
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 2 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2004- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterSep 22, 2024- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 07, 2022This variant is present in population databases (rs104894168, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 15505824, 28749478). ClinVar contains an entry for this variant (Variation ID: 1835). Studies have shown that this premature translational stop signal alters MRPS16 gene expression (PMID: 18539099). 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 sequence change creates a premature translational stop signal (p.Arg111*) in the MRPS16 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the MRPS16 protein. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.93
D
MutationTaster
Benign
1.0
A;A;A;A
Vest4
0.21
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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: rs104894168; hg19: chr10-75010693; API