chr12-6492309-G-C

Position:

• chr12-6492309-G-C

Variant summary

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

The NM_016497.4(MRPL51):​c.349C>G​(p.Leu117Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,504 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: 6.8e-7 (0 hom.)
• Consequence: MRPL51 NM_016497.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74

Genes affected

MRPL51 (HGNC:14044): (mitochondrial ribosomal protein L51) 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. Pseudogenes corresponding to this gene are found on chromosomes 4p and 21q. [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, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPL51	NM_016497.4	c.349C>G	p.Leu117Val	missense_variant	3/3	ENST00000229238.5	NP_057581.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL51	ENST00000229238.5	c.349C>G	p.Leu117Val	missense_variant	3/3	1	NM_016497.4	ENSP00000229238.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460504 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726580

Gnomad4 AFR exome AF: 0.0000300

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;T;.;T;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;.;D;.;D;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.046	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.0	D;.;.;.;.;.;.
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.82
MutPred		0.76		Gain of methylation at K112 (P = 0.0713);.;.;.;.;.;.;
MVP		0.74
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.91

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: rs11380; hg19: chr12-6601475; COSMIC: COSV57520019; COSMIC: COSV57520019;