chr21-25599840-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017446.4(MRPL39):c.547G>A(p.Val183Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

MRPL39
NM_017446.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034297198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL39	NM_017446.4 link	c.547G>A	p.Val183Ile	missense_variant	Exon 5 of 10	ENST00000352957.9	NP_059142.3	Q9NYK5-1
MRPL39	NM_080794.4 link	c.547G>A	p.Val183Ile	missense_variant	Exon 5 of 11		NP_542984.3	Q9NYK5-2
MRPL39	XM_006724026.5 link	c.547G>A	p.Val183Ile	missense_variant	Exon 5 of 10		XP_006724089.1	Q9NYK5-2
MRPL39	XM_011529651.3 link	c.421G>A	p.Val141Ile	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>A	p.Val183Ile	missense_variant	Exon 5 of 10	1	NM_017446.4	ENSP00000284967.7	Q9NYK5-1
MRPL39	ENST00000307301.11 link	c.547G>A	p.Val183Ile	missense_variant	Exon 5 of 11	5		ENSP00000305682.7	Q9NYK5-2
MRPL39	ENST00000419219.1 link	c.521-4G>A		splice_region_variant, intron_variant	Intron 4 of 7	5		ENSP00000404426.1	C9JG87

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000598

AC:

AN:

250940

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.000617

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461378

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000184

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000196

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.547G>A (p.V183I) alteration is located in exon 5 (coding exon 5) of the MRPL39 gene. This alteration results from a G to A substitution at nucleotide position 547, causing the valine (V) at amino acid position 183 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.011

T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.0067

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.59

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.55

N;N

REVEL

Benign

0.092

Sift

Benign

0.35

T;T

Sift4G

Benign

0.10

T;T

Polyphen

0.70

P;B

Vest4

0.23

MVP

0.23

MPC

0.037

ClinPred

0.043

GERP RS

4.4

Varity_R

0.064

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over