rs761373912

Variant names:

• chr21-25601452-A-C
• rs761373912
• NM_017446.4:c.436T>G

Your query was ambiguous. Multiple possible variants found:

• chr21-25601452-A-C
• chr21-25601452-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017446.4(MRPL39):​c.436T>G​(p.Cys146Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 7.0e-7 (0 hom.)
• Consequence: MRPL39 NM_017446.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.92

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL39	NM_017446.4	c.436T>G	p.Cys146Gly	missense_variant	Exon 4 of 10	ENST00000352957.9	NP_059142.3
MRPL39	NM_080794.4	c.436T>G	p.Cys146Gly	missense_variant	Exon 4 of 11		NP_542984.3
MRPL39	XM_006724026.5	c.436T>G	p.Cys146Gly	missense_variant	Exon 4 of 10		XP_006724089.1
MRPL39	XM_011529651.3	c.310T>G	p.Cys104Gly	missense_variant	Exon 4 of 10		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL39	ENST00000352957.9	c.436T>G	p.Cys146Gly	missense_variant	Exon 4 of 10	1	NM_017446.4	ENSP00000284967.7
MRPL39	ENST00000307301.11	c.436T>G	p.Cys146Gly	missense_variant	Exon 4 of 11	5		ENSP00000305682.7
MRPL39	ENST00000419219.1	c.436T>G	p.Cys146Gly	missense_variant	Exon 4 of 8	5		ENSP00000404426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000420 AC: 1 AN: 238364 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128950

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000914

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437164 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 714208

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: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.91	P;P;.
Vest4		0.84
MutPred		0.80		Gain of MoRF binding (P = 0.0923);Gain of MoRF binding (P = 0.0923);Gain of MoRF binding (P = 0.0923);
MVP		0.71
MPC		0.27
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.76

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: rs761373912; hg19: chr21-26973764;