Genetic Variant MRPS34:p.Trp55Ser (chr16-1772956-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_023936.2(MRPS34):c.164G>C(p.Trp55Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000771 in 1,297,392 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W55L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

MRPS34
NM_023936.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.33

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS34	NM_023936.2 link	c.164G>C	p.Trp55Ser	missense_variant	Exon 1 of 3	ENST00000397375.7	NP_076425.1	P82930
EME2	NM_001257370.2 link	c.-272C>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000568449.7	NP_001244299.1	A4GXA9-1
MRPS34	NM_001300900.2 link	c.164G>C	p.Trp55Ser	missense_variant	Exon 1 of 3		NP_001287829.1	P82930C9JJ19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MRPS34	ENST00000397375.7 link	c.164G>C	p.Trp55Ser	missense_variant	Exon 1 of 3	1	NM_023936.2	ENSP00000380531.3	P82930
MRPS34	ENST00000177742.7 link	c.164G>C	p.Trp55Ser	missense_variant	Exon 1 of 3	1		ENSP00000177742.3	C9JJ19
EME2	ENST00000568449.7 link	c.-272C>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_001257370.2	ENSP00000457353.1	A4GXA9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.71e-7

AC:

AN:

1297392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

634696

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25384

American (AMR)

AF:

0.00

AC:

AN:

20366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19308

East Asian (EAS)

AF:

0.00

AC:

AN:

31112

South Asian (SAS)

AF:

0.0000152

AC:

AN:

65766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4898

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1037552

Other (OTH)

AF:

0.00

AC:

AN:

53538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.88

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.4

.;M

PhyloP100

4.3

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.30

B;B

Vest4

0.32

MutPred

0.67

Gain of disorder (P = 1e-04);Gain of disorder (P = 1e-04);

MVP

0.47

MPC

2.2

ClinPred

0.98

GERP RS

4.2

PromoterAI

-0.047

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.71

gMVP

0.85

Mutation Taster

=21/79

disease causing

(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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16-1772956-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over