Genetic Variant NM_017446.4:c.547G>T (chr21-25599840-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017446.4(MRPL39):c.547G>T(p.Val183Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MRPL39
NM_017446.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.283

Variant links:

Genes affected

MRPL39 (HGNC:14027): (mitochondrial ribosomal protein L39) 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. Two transcript variants encoding distinct isoforms have been described. A pseudogene corresponding to this gene is found on chromosome 5q. [provided by RefSeq, Jul 2008]

MRPL39 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40164286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL39	NM_017446.4 link	c.547G>T	p.Val183Leu	missense_variant	Exon 5 of 10	ENST00000352957.9	NP_059142.3	Q9NYK5-1
MRPL39	NM_080794.4 link	c.547G>T	p.Val183Leu	missense_variant	Exon 5 of 11		NP_542984.3	Q9NYK5-2
MRPL39	XM_006724026.5 link	c.547G>T	p.Val183Leu	missense_variant	Exon 5 of 10		XP_006724089.1	Q9NYK5-2
MRPL39	XM_011529651.3 link	c.421G>T	p.Val141Leu	missense_variant	Exon 5 of 10		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MRPL39	ENST00000352957.9 link	c.547G>T	p.Val183Leu	missense_variant	Exon 5 of 10	1	NM_017446.4	ENSP00000284967.7	Q9NYK5-1
MRPL39	ENST00000307301.11 link	c.547G>T	p.Val183Leu	missense_variant	Exon 5 of 11	5		ENSP00000305682.7	Q9NYK5-2
MRPL39	ENST00000419219.1 link	c.521-4G>T		splice_region_variant, intron_variant	Intron 4 of 7	5		ENSP00000404426.1	C9JG87

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461380

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

T;.

Eigen

Benign

0.029

Eigen_PC

Benign

0.052

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.40

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.8

L;L

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.17

Sift

Benign

0.11

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.71

P;P

Vest4

0.38

MutPred

0.74

Gain of ubiquitination at K188 (P = 0.1306);Gain of ubiquitination at K188 (P = 0.1306);

MVP

0.54

MPC

0.046

ClinPred

0.88

GERP RS

4.4

Varity_R

0.29

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over