rs145183319

Variant names:

• chr3-131462785-G-A
• rs145183319
• NM_007208.4:c.985C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_007208.4(MRPL3):​c.985C>T​(p.Pro329Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000169 in 1,612,932 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: MRPL3 NM_007208.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.25
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012918562).
• BP6: Variant 3-131462785-G-A is Benign according to our data. Variant chr3-131462785-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1203624.

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.985C>T	p.Pro329Ser	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.985C>T	p.Pro329Ser	missense	Exon 10 of 10	ENSP00000264995.2	P09001
	MRPL3	ENST00000425847.6	TSL:2	c.1066C>T	p.Pro356Ser	missense	Exon 11 of 11	ENSP00000398536.2	E7ETU7
	MRPL3	ENST00000511168.5	TSL:2	c.1027C>T	p.Pro343Ser	missense	Exon 10 of 10	ENSP00000424107.1	H0Y9G6

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00722

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000319 AC: 80 AN: 250402 AF XY: 0.000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00627

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000884

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000167 AC: 244 AN: 1460814 Hom.: 1 Cov.: 30 AF XY: 0.000183 AC XY: 133 AN XY: 726698

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00698 AC: 182 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111364

Other (OTH) AF: 0.000630 AC: 38 AN: 60346

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00722 AC: 25 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000510 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000198 AC: 24

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.3
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.22
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.041	D
Polyphen		0.52	P
Vest4		0.28
MVP		0.90
MPC		0.22
ClinPred		0.30	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.50
Mutation Taster		=80/20	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: rs145183319; hg19: chr3-131181629; COSMIC: COSV53913223; COSMIC: COSV53913223;