21-25592891-G-A

Variant names:

• chr21-25592891-G-A
• NM_017446.4:c.842C>T

Variant summary

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

The NM_017446.4(MRPL39):​c.842C>T​(p.Ser281Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 NM_017446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.52

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 rank	MANE	Protein	UniProt
MRPL39	NM_017446.4	c.842C>T	p.Ser281Leu	missense_variant	Exon 8 of 10	ENST00000352957.9	NP_059142.3
MRPL39	NM_080794.4	c.842C>T	p.Ser281Leu	missense_variant	Exon 8 of 11		NP_542984.3
MRPL39	XM_006724026.5	c.842C>T	p.Ser281Leu	missense_variant	Exon 8 of 10		XP_006724089.1
MRPL39	XM_011529651.3	c.716C>T	p.Ser239Leu	missense_variant	Exon 8 of 10		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL39	ENST00000352957.9	c.842C>T	p.Ser281Leu	missense_variant	Exon 8 of 10	1	NM_017446.4	ENSP00000284967.7
MRPL39	ENST00000307301.11	c.842C>T	p.Ser281Leu	missense_variant	Exon 8 of 11	5		ENSP00000305682.7
MRPL39	ENST00000419219.1	c.812C>T	p.Ser271Leu	missense_variant	Exon 8 of 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: 1460578 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 726688

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

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.842C>T (p.S281L) alteration is located in exon 8 (coding exon 8) of the MRPL39 gene. This alteration results from a C to T substitution at nucleotide position 842, causing the serine (S) at amino acid position 281 to be replaced by a leucine (L). 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	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.20
Sift	Benign	0.054	T;T;T
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.12	B;B;.
Vest4		0.62
MutPred		0.53		Loss of disorder (P = 0.0503);Loss of disorder (P = 0.0503);.;
MVP		0.74
MPC		0.082
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.50
gMVP		0.59

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: chr21-26965203;