chr21-25601389-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_017446.4(MRPL39):c.499G>A(p.Val167Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,610,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MRPL39
NM_017446.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.533

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

MRPL39 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.37309 (below the threshold of 3.09). Trascript score misZ: -0.3663 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.086749464).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017446.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL39	NM_017446.4	MANE Select	c.499G>A	p.Val167Ile	missense	Exon 4 of 10	NP_059142.3
	MRPL39	NM_080794.4		c.499G>A	p.Val167Ile	missense	Exon 4 of 11	NP_542984.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRPL39	ENST00000352957.9	TSL:1 MANE Select	c.499G>A	p.Val167Ile	missense	Exon 4 of 10	ENSP00000284967.7	Q9NYK5-1
MRPL39	ENST00000307301.11	TSL:5	c.499G>A	p.Val167Ile	missense	Exon 4 of 11	ENSP00000305682.7	Q9NYK5-2
MRPL39	ENST00000925346.1		c.517G>A	p.Val173Ile	missense	Exon 4 of 10	ENSP00000595405.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250550

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1458402

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39522

South Asian (SAS)

AF:

0.00

AC:

AN:

85840

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1110006

Other (OTH)

AF:

0.00

AC:

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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

AF:

0.00000658

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.011

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.83

M_CAP

Benign

0.0015

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

PhyloP100

0.53

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.22

REVEL

Benign

0.033

Sift

Benign

0.64

Sift4G

Benign

0.48

Polyphen

0.0

Vest4

0.15

MutPred

0.39

Loss of catalytic residue at E171 (P = 0.3857)

MVP

0.088

MPC

0.032

ClinPred

0.13

GERP RS

4.2

Varity_R

0.030

gMVP

0.14

Mutation Taster

=87/13

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over