21-25587730-C-G

Variant names:

• chr21-25587730-C-G
• NM_017446.4:c.969+1105G>C

Variant summary

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

The NM_080794.4(MRPL39):​c.1029G>C​(p.Glu343Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRPL39 NM_080794.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.116

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=0.081929296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL39	NM_017446.4	c.969+1105G>C		intron_variant	Intron 9 of 9	ENST00000352957.9	NP_059142.3
MRPL39	NM_080794.4	c.1029G>C	p.Glu343Asp	missense_variant	Exon 10 of 11		NP_542984.3
MRPL39	XM_006724026.5	c.1029G>C	p.Glu343Asp	missense_variant	Exon 10 of 10		XP_006724089.1
MRPL39	XM_011529651.3	c.843+1105G>C		intron_variant	Intron 9 of 9		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL39	ENST00000352957.9	c.969+1105G>C		intron_variant	Intron 9 of 9	1	NM_017446.4	ENSP00000284967.7
MRPL39	ENST00000307301.11	c.1029G>C	p.Glu343Asp	missense_variant	Exon 10 of 11	5		ENSP00000305682.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1029G>C (p.E343D) alteration is located in exon 10 (coding exon 10) of the MRPL39 gene. This alteration results from a G to C substitution at nucleotide position 1029, causing the glutamic acid (E) at amino acid position 343 to be replaced by an aspartic acid (D). 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
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.4
DANN	Benign	0.95
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.029
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.31	T
Polyphen		0.027	B
Vest4		0.24
MutPred		0.34		Loss of disorder (P = 0.1402);
MVP		0.31
MPC		0.032
ClinPred		0.38	T
GERP RS		-0.32
gMVP		0.29

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: chr21-26960042;