3-131468101-C-G

Variant names:

• chr3-131468101-C-G
• rs758835610
• NM_007208.4:c.884G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007208.4(MRPL3):​c.884G>C​(p.Cys295Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000783 in 1,405,480 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. C295C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000078 (0 hom.)
• Consequence: MRPL3 NM_007208.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.94
• Publications: 0 publications found

Genes affected

MRPL3 (HGNC:10379): (mitochondrial ribosomal protein L3) 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 that belongs to the L3P ribosomal protein family. A pseudogene corresponding to this gene is found on chromosome 13q. [provided by RefSeq, Jul 2008]

MRPL3 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 9

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL3	NM_007208.4	MANE Select	c.884G>C	p.Cys295Ser	missense	Exon 9 of 10	NP_009139.1	P09001

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL3	ENST00000264995.8	TSL:1 MANE Select	c.884G>C	p.Cys295Ser	missense	Exon 9 of 10	ENSP00000264995.2	P09001
	MRPL3	ENST00000425847.6	TSL:2	c.965G>C	p.Cys322Ser	missense	Exon 10 of 11	ENSP00000398536.2	E7ETU7
	MRPL3	ENST00000511168.5	TSL:2	c.926G>C	p.Cys309Ser	missense	Exon 9 of 10	ENSP00000424107.1	H0Y9G6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000936 AC: 2 AN: 213712 AF XY: 0.00000859

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000197

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000783 AC: 11 AN: 1405480 Hom.: 0 Cov.: 28 AF XY: 0.00000858 AC XY: 6 AN XY: 699534

African (AFR) AF: 0.00 AC: 0 AN: 30382

American (AMR) AF: 0.0000285 AC: 1 AN: 35100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24322

East Asian (EAS) AF: 0.00 AC: 0 AN: 37764

South Asian (SAS) AF: 0.00 AC: 0 AN: 76956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 0.00000922 AC: 10 AN: 1084912

Other (OTH) AF: 0.00 AC: 0 AN: 57920

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Combined oxidative phosphorylation defect type 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.26
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0096	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.58	N
PhyloP100		6.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.019	B
Vest4		0.64
MutPred		0.57		Gain of disorder (P = 2e-04)
MVP		0.71
MPC		0.12
ClinPred		0.21	T
GERP RS		5.7
Varity_R		0.51
gMVP		0.70
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs758835610; hg19: chr3-131186945;