Genetic Variant MRPS34:p.Leu79Pro (chr16-1772884-A-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.236T>C(p.Leu79Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000769 in 1,299,920 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. L79R) 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: 5.04

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.236T>C	p.Leu79Pro	missense_variant	Exon 1 of 3	ENST00000397375.7	NP_076425.1	P82930
EME2	NM_001257370.2 link	c.-344A>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000568449.7	NP_001244299.1	A4GXA9-1
MRPS34	NM_001300900.2 link	c.236T>C	p.Leu79Pro	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.236T>C	p.Leu79Pro	missense_variant	Exon 1 of 3	1	NM_023936.2	ENSP00000380531.3	P82930
MRPS34	ENST00000177742.7 link	c.236T>C	p.Leu79Pro	missense_variant	Exon 1 of 3	1		ENSP00000177742.3	C9JJ19
EME2	ENST00000568449.7 link	c.-344A>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_001257370.2	ENSP00000457353.1	A4GXA9-1
MRPS34	ENST00000569585.1 link	n.-186T>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.69e-7

AC:

AN:

1299920

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

634786

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27570

American (AMR)

AF:

0.00

AC:

AN:

21708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19482

East Asian (EAS)

AF:

0.00

AC:

AN:

33384

South Asian (SAS)

AF:

0.00

AC:

AN:

66712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4364

European-Non Finnish (NFE)

AF:

9.60e-7

AC:

AN:

1041744

Other (OTH)

AF:

0.00

AC:

AN:

53988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

5.0

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;D

Vest4

0.64

MutPred

0.69

Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);

MVP

0.16

MPC

3.6

ClinPred

0.99

GERP RS

3.7

PromoterAI

0.027

Neutral

(source)

Varity_R

0.77

gMVP

0.89

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over