3-131462839-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_007208.4(MRPL3):c.931G>A(p.Gly311Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,611,402 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (20 hom.)
• Consequence: MRPL3 NM_007208.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: -0.237

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067156255).
• BP6: Variant 3-131462839-C-T is Benign according to our data. Variant chr3-131462839-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 374558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL3	NM_007208.4	c.931G>A	p.Gly311Ser	missense_variant	10/10	ENST00000264995.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL3	ENST00000264995.8	c.931G>A	p.Gly311Ser	missense_variant	10/10	1	NM_007208.4	P1
MRPL3	ENST00000425847.6	c.1012G>A	p.Gly338Ser	missense_variant	11/11	2
MRPL3	ENST00000511168.5	c.976G>A	p.Gly326Ser	missense_variant	10/10	2
MRPL3	ENST00000510043.1	n.355G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 477 AN: 152002 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000822

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00368 AC: 920 AN: 249772 Hom.: 7 AF XY: 0.00416 AC XY: 561 AN XY: 134998

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00364

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00519

Gnomad OTH exome AF: 0.00773

GnomAD4 exome AF: 0.00335 AC: 4894 AN: 1459282 Hom.: 20 Cov.: 30 AF XY: 0.00354 AC XY: 2571 AN XY: 725978

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00310

Gnomad4 ASJ exome AF: 0.00288

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00400

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00355

Gnomad4 OTH exome AF: 0.00365

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152120 Hom.: 3 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74352

Gnomad4 AFR AF: 0.000819

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00497

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00406 Hom.: 4

Bravo AF: 0.00327

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00376 AC: 456

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MRPL3: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	4.5
Dann	Benign	0.55
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.29	T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.1	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.5	N;N
REVEL	Benign	0.017
Sift	Benign	0.79	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0	B;B
Vest4		0.083
MVP		0.65
MPC		0.066
ClinPred		0.0020	T
GERP RS		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.22

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: rs148679749; hg19: chr3-131181683; COSMIC: COSV53916428; COSMIC: COSV53916428;