21-25593918-G-T

Variant names:

• chr21-25593918-G-T
• rs757104478
• NM_017446.4:c.742C>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.742C>A​(p.Pro248Thr) 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 1,461,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MRPL39 NM_017446.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.849

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=0.07752374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL39	NM_017446.4	c.742C>A	p.Pro248Thr	missense_variant	Exon 7 of 10	ENST00000352957.9	NP_059142.3
MRPL39	NM_080794.4	c.742C>A	p.Pro248Thr	missense_variant	Exon 7 of 11		NP_542984.3
MRPL39	XM_006724026.5	c.742C>A	p.Pro248Thr	missense_variant	Exon 7 of 10		XP_006724089.1
MRPL39	XM_011529651.3	c.616C>A	p.Pro206Thr	missense_variant	Exon 7 of 10		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL39	ENST00000352957.9	c.742C>A	p.Pro248Thr	missense_variant	Exon 7 of 10	1	NM_017446.4	ENSP00000284967.7
MRPL39	ENST00000307301.11	c.742C>A	p.Pro248Thr	missense_variant	Exon 7 of 11	5		ENSP00000305682.7
MRPL39	ENST00000419219.1	c.712C>A	p.Pro238Thr	missense_variant	Exon 7 of 8	5		ENSP00000404426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461260 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726936

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000193 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T;.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.048
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.074	B;B;.
Vest4		0.10
MVP		0.53
MPC		0.045
ClinPred		0.16	T
GERP RS		0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs757104478; hg19: chr21-26966230;