1-175014763-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_022100.3(MRPS14):​c.293G>A​(p.Arg98His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,032 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MRPS14
NM_022100.3 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.71
Variant links:
Genes affected
MRPS14 (HGNC:14049): (mitochondrial ribosomal protein S14) 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 S14P family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2010]

Genome browser will be placed here

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, 0.823

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MRPS14NM_022100.3 linkc.293G>A p.Arg98His missense_variant Exon 3 of 3 ENST00000476371.1 NP_071383.1 O60783
MRPS14NR_037606.2 linkn.402G>A non_coding_transcript_exon_variant Exon 3 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MRPS14ENST00000476371.1 linkc.293G>A p.Arg98His missense_variant Exon 3 of 3 1 NM_022100.3 ENSP00000420714.1 O60783
MRPS14ENST00000367677.3 linkn.*202G>A non_coding_transcript_exon_variant Exon 3 of 3 1 ENSP00000431220.1 F2Z361
MRPS14ENST00000367677.3 linkn.*202G>A 3_prime_UTR_variant Exon 3 of 3 1 ENSP00000431220.1 F2Z361
MRPS14ENST00000498253.1 linkn.62G>A non_coding_transcript_exon_variant Exon 1 of 3 2

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.000103
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251158
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135812
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461880
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
727244
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.000162
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jan 13, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 98 of the MRPS14 protein (p.Arg98His). This variant is present in population databases (rs149343934, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MRPS14-related conditions. ClinVar contains an entry for this variant (Variation ID: 2892030). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.69
D
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Benign
0.013
T
MetaRNN
Pathogenic
0.82
D
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
1.8
L
PrimateAI
Pathogenic
0.92
D
PROVEAN
Uncertain
-4.0
D
REVEL
Uncertain
0.51
Sift
Benign
0.041
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.99
D
Vest4
0.86
MVP
0.40
MPC
0.66
ClinPred
0.81
D
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.34
gMVP
0.86

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: rs149343934; hg19: chr1-174983899; COSMIC: COSV62880676; COSMIC: COSV62880676; API