21-25597371-T-C

Position:

chr21-25597371-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017446.4(MRPL39):c.632A>G(p.Tyr211Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000237 in 1,602,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MRPL39
NM_017446.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.120749).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MRPL39	NM_017446.4 linkuse as main transcript	c.632A>G	p.Tyr211Cys	missense_variant	6/10	ENST00000352957.9	NP_059142.3
MRPL39	NM_080794.4 linkuse as main transcript	c.632A>G	p.Tyr211Cys	missense_variant	6/11		NP_542984.3
MRPL39	XM_006724026.5 linkuse as main transcript	c.632A>G	p.Tyr211Cys	missense_variant	6/10		XP_006724089.1
MRPL39	XM_011529651.3 linkuse as main transcript	c.506A>G	p.Tyr169Cys	missense_variant	6/10		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL39	ENST00000352957.9 linkuse as main transcript	c.632A>G	p.Tyr211Cys	missense_variant	6/10	1	NM_017446.4	ENSP00000284967	P1	Q9NYK5-1
MRPL39	ENST00000307301.11 linkuse as main transcript	c.632A>G	p.Tyr211Cys	missense_variant	6/11	5		ENSP00000305682		Q9NYK5-2
MRPL39	ENST00000419219.1 linkuse as main transcript	c.602A>G	p.Tyr201Cys	missense_variant	6/8	5		ENSP00000404426

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

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

GnomAD3 exomes

AF:

0.0000411

AC:

AN:

243142

Hom.:

AF XY:

0.0000228

AC XY:

AN XY:

131368

show subpopulations

Gnomad AFR exome

AF:

0.000668

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1450412

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

721628

show subpopulations

Gnomad4 AFR exome

AF:

0.000572

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:

9.05e-7

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.000105

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000386

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

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.632A>G (p.Y211C) alteration is located in exon 6 (coding exon 6) of the MRPL39 gene. This alteration results from a A to G substitution at nucleotide position 632, causing the tyrosine (Y) at amino acid position 211 to be replaced by a cysteine (C). 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

0.060

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

T;.;T

Eigen

Benign

0.099

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.1

L;L;.

MutationTaster

Benign

0.58

N;N

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Benign

0.050

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.93

P;P;.

Vest4

0.23

MVP

0.71

MPC

0.043

ClinPred

0.17

GERP RS

3.0

Varity_R

0.16

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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