chr16-1773083-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_023936.2(MRPS34):c.37G>A(p.Glu13Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,255,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

MRPS34
NM_023936.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 3.40

Publications

2 publications found

Variant links:

Genes affected

MRPS34 (HGNC:16618): (mitochondrial ribosomal protein S34) 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MRPS34 links:

EME2 (HGNC:27289): (essential meiotic structure-specific endonuclease subunit 2) EME2 forms a heterodimer with MUS81 (MIM 606591) that functions as an XPF (MIM 278760)-type flap/fork endonuclease in DNA repair (Ciccia et al., 2007 [PubMed 17289582]).[supplied by OMIM, Mar 2008]

EME2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-1773083-C-T is Pathogenic according to our data. Variant chr16-1773083-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 430585.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MRPS34	NM_023936.2 link	c.37G>A	p.Glu13Lys	missense_variant	Exon 1 of 3	ENST00000397375.7	NP_076425.1
EME2	NM_001257370.2 link	c.-145C>T		5_prime_UTR_variant	Exon 1 of 8	ENST00000568449.7	NP_001244299.1
MRPS34	NM_001300900.2 link	c.37G>A	p.Glu13Lys	missense_variant	Exon 1 of 3		NP_001287829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MRPS34	ENST00000397375.7 link	c.37G>A	p.Glu13Lys	missense_variant	Exon 1 of 3	1	NM_023936.2	ENSP00000380531.3
MRPS34	ENST00000177742.7 link	c.37G>A	p.Glu13Lys	missense_variant	Exon 1 of 3	1		ENSP00000177742.3
EME2	ENST00000568449.7 link	c.-145C>T		5_prime_UTR_variant	Exon 1 of 8	1	NM_001257370.2	ENSP00000457353.1
EME2	ENST00000570069.5 link	n.-243C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000637

AC:

AN:

1255786

Hom.:

Cov.:

AF XY:

0.00000657

AC XY:

AN XY:

608840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24422

American (AMR)

AF:

0.00

AC:

AN:

15080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17596

East Asian (EAS)

AF:

0.0000336

AC:

AN:

29798

South Asian (SAS)

AF:

0.00

AC:

AN:

58652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5080

European-Non Finnish (NFE)

AF:

0.00000492

AC:

AN:

1017272

Other (OTH)

AF:

0.0000386

AC:

AN:

51786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation deficiency 32

Pathogenic:2

Apr 16, 2018

SIB Swiss Institute of Bioinformatics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Likely Pathogenic, for Combined oxidative phosphorylation deficiency 32, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:28777931). -

Sep 16, 2017

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Leigh syndrome

Pathogenic:1

Genetics of Mitochondrial Diseases, Imagine Institute

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.092

T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.3

.;M

PhyloP100

3.4

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.89

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.042

D;D

Polyphen

0.99

D;D

Vest4

0.44

MutPred

0.29

Gain of ubiquitination at E13 (P = 0.0452);Gain of ubiquitination at E13 (P = 0.0452);

MVP

0.43

MPC

2.9

ClinPred

0.96

GERP RS

3.7

PromoterAI

-0.059

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.40

gMVP

0.62

Mutation Taster

=31/69

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over