21-25597366-C-T

Position:

• chr21-25597366-C-T

Variant summary

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

The ENST00000352957.9(MRPL39):​c.637G>A​(p.Asp213Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRPL39 ENST00000352957.9 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPL39	NM_017446.4	c.637G>A	p.Asp213Asn	missense_variant	6/10	ENST00000352957.9	NP_059142.3
MRPL39	NM_080794.4	c.637G>A	p.Asp213Asn	missense_variant	6/11		NP_542984.3
MRPL39	XM_006724026.5	c.637G>A	p.Asp213Asn	missense_variant	6/10		XP_006724089.1
MRPL39	XM_011529651.3	c.511G>A	p.Asp171Asn	missense_variant	6/10		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL39	ENST00000352957.9	c.637G>A	p.Asp213Asn	missense_variant	6/10	1	NM_017446.4	ENSP00000284967.7
MRPL39	ENST00000307301.11	c.637G>A	p.Asp213Asn	missense_variant	6/11	5		ENSP00000305682.7
MRPL39	ENST00000419219.1	c.607G>A	p.Asp203Asn	missense_variant	6/8	5		ENSP00000404426.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450824 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 721834

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: 0.00

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

Aug 13, 2021

The c.637G>A (p.D213N) alteration is located in exon 6 (coding exon 6) of the MRPL39 gene. This alteration results from a G to A substitution at nucleotide position 637, causing the aspartic acid (D) at amino acid position 213 to be replaced by an asparagine (N). 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	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T;.;T
Eigen	Benign	0.094
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.18
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.54	P;P;.
Vest4		0.45
MutPred		0.79		Gain of ubiquitination at K212 (P = 0.1497);Gain of ubiquitination at K212 (P = 0.1497);.;
MVP		0.72
MPC		0.15
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.45
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-26969678;