Genetic Variant NM_014050.4:c.139G>T (chr12-93479392-G-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_014050.4(MRPL42):c.139G>T(p.Val47Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,080 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. V47A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MRPL42
NM_014050.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.80

Publications

0 publications found

Variant links:

Genes affected

MRPL42 (HGNC:14493): (mitochondrial ribosomal protein L42) 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 protein identified as belonging to both the 28S and the 39S subunits. Alternative splicing results in multiple transcript variants. Pseudogenes corresponding to this gene are found on chromosomes 4q, 6p, 6q, 7p, and 15q. [provided by RefSeq, May 2011]

MRPL42 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, 0.817

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014050.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRPL42	NM_014050.4	MANE Select	c.139G>T	p.Val47Leu	missense	Exon 4 of 6	NP_054769.1	Q9Y6G3
MRPL42	NM_172177.5		c.139G>T	p.Val47Leu	missense	Exon 4 of 6	NP_751917.1	Q9Y6G3
MRPL42	NR_038159.2		n.297G>T		non_coding_transcript_exon	Exon 5 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRPL42	ENST00000549982.6	TSL:1 MANE Select	c.139G>T	p.Val47Leu	missense	Exon 4 of 6	ENSP00000449884.1	Q9Y6G3
MRPL42	ENST00000358678.7	TSL:1	n.*88G>T		non_coding_transcript_exon	Exon 5 of 7	ENSP00000351506.3	J3KP21
MRPL42	ENST00000358678.7	TSL:1	n.*88G>T		3_prime_UTR	Exon 5 of 7	ENSP00000351506.3	J3KP21

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452080

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722748

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:

33088

American (AMR)

AF:

0.00

AC:

AN:

43788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25840

East Asian (EAS)

AF:

0.00

AC:

AN:

39464

South Asian (SAS)

AF:

0.00

AC:

AN:

85654

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106590

Other (OTH)

AF:

0.00

AC:

AN:

59826

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Benign

0.0063

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.065

MutationAssessor

Pathogenic

3.0

PhyloP100

8.8

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.58

Sift

Uncertain

0.014

Sift4G

Uncertain

0.056

Polyphen

0.99

Vest4

0.84

MutPred

0.64

Gain of catalytic residue at E48 (P = 0.0058)

MVP

0.43

MPC

0.19

ClinPred

0.94

GERP RS

5.3

Varity_R

0.45

gMVP

0.37

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over