21-25606523-T-C

Position:

• chr21-25606523-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017446.4(MRPL39):​c.206A>G​(p.His69Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MRPL39 NM_017446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2882309).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPL39	NM_017446.4	c.206A>G	p.His69Arg	missense_variant	2/10	ENST00000352957.9	NP_059142.3
MRPL39	NM_080794.4	c.206A>G	p.His69Arg	missense_variant	2/11		NP_542984.3
MRPL39	XM_006724026.5	c.206A>G	p.His69Arg	missense_variant	2/10		XP_006724089.1
MRPL39	XM_011529651.3	c.80A>G	p.His27Arg	missense_variant	2/10		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL39	ENST00000352957.9	c.206A>G	p.His69Arg	missense_variant	2/10	1	NM_017446.4	ENSP00000284967	P1
MRPL39	ENST00000307301.11	c.206A>G	p.His69Arg	missense_variant	2/11	5		ENSP00000305682
MRPL39	ENST00000419219.1	c.206A>G	p.His69Arg	missense_variant	2/8	5		ENSP00000404426

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461806 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Feb 09, 2023

The c.206A>G (p.H69R) alteration is located in exon 2 (coding exon 2) of the MRPL39 gene. This alteration results from a A to G substitution at nucleotide position 206, causing the histidine (H) at amino acid position 69 to be replaced by an arginine (R). 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	0.29
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;T
Eigen	Benign	0.089
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	0.60	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.095
Sift	Uncertain	0.023	D;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.44	B;P;.
Vest4		0.48
MutPred		0.36		Gain of MoRF binding (P = 0.0235);Gain of MoRF binding (P = 0.0235);Gain of MoRF binding (P = 0.0235);
MVP		0.37
MPC		0.20
ClinPred		0.97	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs115482384; hg19: chr21-26978835;