Genetic Variant MRPL34:p.Gln54Leu (chr19-17306261-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_023937.4(MRPL34):c.161A>T(p.Gln54Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. Q54R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MRPL34
NM_023937.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.43

Publications

0 publications found

Variant links:

Genes affected

MRPL34 (HGNC:14488): (mitochondrial ribosomal protein L34) 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 39S subunit protein. [provided by RefSeq, Jul 2008]

MRPL34 links:

ABHD8 (HGNC:23759): (abhydrolase domain containing 8) This gene is upstream of, and in a head-to-head orientation with the gene for the mitochondrial ribosomal protein L34. The predicted protein contains alpha/beta hydrolase fold and secretory lipase domains. [provided by RefSeq, Jul 2008]

ABHD8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL34	NM_023937.4 link	c.161A>T	p.Gln54Leu	missense_variant	Exon 2 of 2	ENST00000252602.2	NP_076426.1	Q9BQ48A0A024R7J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL34	ENST00000252602.2 link	c.161A>T	p.Gln54Leu	missense_variant	Exon 2 of 2	1	NM_023937.4	ENSP00000252602.1		Q9BQ48

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1449152

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720090

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33270

American (AMR)

AF:

0.00

AC:

AN:

43042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25810

East Asian (EAS)

AF:

0.00

AC:

AN:

39096

South Asian (SAS)

AF:

0.00

AC:

AN:

84726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5464

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106872

Other (OTH)

AF:

0.00

AC:

AN:

59734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

.;D;D;D

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

D;.;.;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

-0.081

PhyloP100

8.4

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.9

.;.;.;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0030

.;.;.;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.59

MutPred

0.77

.;Loss of disorder (P = 0.042);Loss of disorder (P = 0.042);Loss of disorder (P = 0.042);

MVP

0.34

MPC

1.3

ClinPred

1.0

GERP RS

5.7

PromoterAI

-0.045

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.84

gMVP

0.44

Mutation Taster

=35/65

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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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