rs754377823

Variant names:

• chr3-131462791-C-T
• rs754377823
• NM_007208.4:c.979G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007208.4(MRPL3):​c.979G>A​(p.Glu327Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E327E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MRPL3 NM_007208.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1825827).

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.979G>A	p.Glu327Lys	missense	Exon 10 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.979G>A	p.Glu327Lys	missense	Exon 10 of 10	ENSP00000264995.2	P09001
	MRPL3	ENST00000425847.6	TSL:2	c.1060G>A	p.Glu354Lys	missense	Exon 11 of 11	ENSP00000398536.2	E7ETU7
	MRPL3	ENST00000511168.5	TSL:2	c.1021G>A	p.Glu341Lys	missense	Exon 10 of 10	ENSP00000424107.1	H0Y9G6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250408 AF XY: 0.0000148

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460812 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726698

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111376

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.36	T
Sift4G	Benign	0.80	T
Polyphen		0.0030	B
Vest4		0.23
MutPred		0.40		Gain of ubiquitination at E354 (P = 0.0085)
MVP		0.84
MPC		0.075
ClinPred		0.70	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.47
Mutation Taster		=75/25	polymorphism

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: rs754377823; hg19: chr3-131181635;