NM_015956.3:c.509G>C

Variant names:

• chr19-10258285-G-C
• NM_015956.3:c.509G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015956.3(MRPL4):​c.509G>C​(p.Arg170Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MRPL4 NM_015956.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.33

Genes affected

MRPL4 (HGNC:14276): (mitochondrial ribosomal protein L4) 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. Sequence analysis identified alternatively spliced variants that encode different protein isoforms. [provided by RefSeq, Jul 2008]

LIMASI (HGNC:56357): (lncRNA inflammatory and mucous response associated, antisense to ICAM1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL4	NM_015956.3	c.509G>C	p.Arg170Pro	missense_variant	Exon 6 of 9	ENST00000253099.11	NP_057040.2
MRPL4	NM_001411149.1	c.509G>C	p.Arg170Pro	missense_variant	Exon 6 of 9		NP_001398078.1
MRPL4	NM_146387.2	c.509G>C	p.Arg170Pro	missense_variant	Exon 7 of 10		NP_666499.1
MRPL4	NM_146388.2	c.509G>C	p.Arg170Pro	missense_variant	Exon 6 of 8		NP_666500.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL4	ENST00000253099.11	c.509G>C	p.Arg170Pro	missense_variant	Exon 6 of 9	1	NM_015956.3	ENSP00000253099.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;T;.;T;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;.;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	4.0	.;H;H;H;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.3	.;D;D;.;D;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	.;D;D;.;D;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.;.
Vest4		0.97, 0.97, 0.98, 0.98
MutPred		0.71		Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);.;.;
MVP		0.42
MPC		1.4
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.90

Splicing

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: chr19-10368961;