Genetic Variant MRPL39:p.Met148Thr (chr21-25601445-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017446.4(MRPL39):c.443T>C(p.Met148Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,445,260 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MRPL39
NM_017446.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.92

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL39	NM_017446.4 link	c.443T>C	p.Met148Thr	missense_variant	Exon 4 of 10	ENST00000352957.9	NP_059142.3	Q9NYK5-1
MRPL39	NM_080794.4 link	c.443T>C	p.Met148Thr	missense_variant	Exon 4 of 11		NP_542984.3	Q9NYK5-2
MRPL39	XM_006724026.5 link	c.443T>C	p.Met148Thr	missense_variant	Exon 4 of 10		XP_006724089.1	Q9NYK5-2
MRPL39	XM_011529651.3 link	c.317T>C	p.Met106Thr	missense_variant	Exon 4 of 10		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MRPL39	ENST00000352957.9 link	c.443T>C	p.Met148Thr	missense_variant	Exon 4 of 10	1	NM_017446.4	ENSP00000284967.7	Q9NYK5-1
MRPL39	ENST00000307301.11 link	c.443T>C	p.Met148Thr	missense_variant	Exon 4 of 11	5		ENSP00000305682.7	Q9NYK5-2
MRPL39	ENST00000419219.1 link	c.443T>C	p.Met148Thr	missense_variant	Exon 4 of 8	5		ENSP00000404426.1	C9JG87

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245594

Hom.:

AF XY:

0.00000753

AC XY:

AN XY:

132888

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1445260

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718618

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.443T>C (p.M148T) alteration is located in exon 4 (coding exon 4) of the MRPL39 gene. This alteration results from a T to C substitution at nucleotide position 443, causing the methionine (M) at amino acid position 148 to be replaced by a threonine (T). 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

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.66

D;D;D

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.1

M;M;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.023

D;D;D

Sift4G

Benign

0.096

T;T;T

Polyphen

0.87

P;P;.

Vest4

0.86

MutPred

0.65

Loss of stability (P = 0.0233);Loss of stability (P = 0.0233);Loss of stability (P = 0.0233);

MVP

0.67

MPC

0.068

ClinPred

0.73

GERP RS

5.1

Varity_R

0.63

gMVP

0.52

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

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