chr16-1772884-A-C

Variant names:

• chr16-1772884-A-C
• rs975567721
• NM_023936.2:c.236T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_023936.2(MRPS34):​c.236T>G​(p.Leu79Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000022 in 1,452,160 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: MRPS34 NM_023936.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

Genes affected

MRPS34 (HGNC:16618): (mitochondrial ribosomal protein S34) 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 28S subunit protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

EME2 (HGNC:27289): (essential meiotic structure-specific endonuclease subunit 2) EME2 forms a heterodimer with MUS81 (MIM 606591) that functions as an XPF (MIM 278760)-type flap/fork endonuclease in DNA repair (Ciccia et al., 2007 [PubMed 17289582]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS34	NM_023936.2	c.236T>G	p.Leu79Arg	missense_variant	Exon 1 of 3	ENST00000397375.7	NP_076425.1
EME2	NM_001257370.2	c.-344A>C		5_prime_UTR_variant	Exon 1 of 8	ENST00000568449.7	NP_001244299.1
MRPS34	NM_001300900.2	c.236T>G	p.Leu79Arg	missense_variant	Exon 1 of 3		NP_001287829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPS34	ENST00000397375.7	c.236T>G	p.Leu79Arg	missense_variant	Exon 1 of 3	1	NM_023936.2	ENSP00000380531.3
MRPS34	ENST00000177742.7	c.236T>G	p.Leu79Arg	missense_variant	Exon 1 of 3	1		ENSP00000177742.3
EME2	ENST00000568449	c.-344A>C		5_prime_UTR_variant	Exon 1 of 8	1	NM_001257370.2	ENSP00000457353.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152240 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

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

GnomAD4 exome AF: 0.0000215 AC: 28 AN: 1299920 Hom.: 0 Cov.: 62 AF XY: 0.0000189 AC XY: 12 AN XY: 634786

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000259

Gnomad4 OTH exome AF: 0.0000185

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152240 Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.236T>G (p.L79R) alteration is located in exon 1 (coding exon 1) of the MRPS34 gene. This alteration results from a T to G substitution at nucleotide position 236, causing the leucine (L) at amino acid position 79 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.26
Sift	Benign	0.033	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;D
Vest4		0.57
MutPred		0.64		Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);
MVP		0.15
MPC		3.4
ClinPred		0.97	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.48
gMVP		0.82

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: rs975567721; hg19: chr16-1822885;