21-25599832-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017446.4(MRPL39):c.555G>T(p.Leu185Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000449 in 1,613,684 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: MRPL39 NM_017446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22

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]

ACMG classification

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=0.14676645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL39	NM_017446.4	c.555G>T	p.Leu185Phe	missense_variant	5/10	ENST00000352957.9
MRPL39	NM_080794.4	c.555G>T	p.Leu185Phe	missense_variant	5/11
MRPL39	XM_006724026.5	c.555G>T	p.Leu185Phe	missense_variant	5/10
MRPL39	XM_011529651.3	c.429G>T	p.Leu143Phe	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL39	ENST00000352957.9	c.555G>T	p.Leu185Phe	missense_variant	5/10	1	NM_017446.4	P1
MRPL39	ENST00000307301.11	c.555G>T	p.Leu185Phe	missense_variant	5/11	5
MRPL39	ENST00000419219.1	c.525G>T	p.Leu175Phe	missense_variant	5/8	5

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 250902 Hom.: 0 AF XY: 0.000368 AC XY: 50 AN XY: 135708

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000785

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000470 AC: 687 AN: 1461420 Hom.: 1 Cov.: 30 AF XY: 0.000525 AC XY: 382 AN XY: 727046

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000529

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74466

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000354 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.555G>T (p.L185F) alteration is located in exon 5 (coding exon 5) of the MRPL39 gene. This alteration results from a G to T substitution at nucleotide position 555, causing the leucine (L) at amino acid position 185 to be replaced by a phenylalanine (F). 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	0.41
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D;D;N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.71
MutPred		0.61		Loss of ubiquitination at K188 (P = 0.0907);Loss of ubiquitination at K188 (P = 0.0907);.;
MVP		0.74
MPC		0.27
ClinPred		0.31	T
GERP RS		5.3
Varity_R		0.54
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs73159712; hg19: chr21-26972144;