chr16-1773083-C-T

Position:

• chr16-1773083-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_023936.2(MRPS34):​c.37G>A​(p.Glu13Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,255,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: MRPS34 NM_023936.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.40

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-1773083-C-T is Pathogenic according to our data. Variant chr16-1773083-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430585.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-1773083-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS34	NM_023936.2	c.37G>A	p.Glu13Lys	missense_variant	1/3	ENST00000397375.7	NP_076425.1
EME2	NM_001257370.2	c.-145C>T		5_prime_UTR_variant	1/8	ENST00000568449.7	NP_001244299.1
MRPS34	NM_001300900.2	c.37G>A	p.Glu13Lys	missense_variant	1/3		NP_001287829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS34	ENST00000397375.7	c.37G>A	p.Glu13Lys	missense_variant	1/3	1	NM_023936.2	ENSP00000380531.3
MRPS34	ENST00000177742.7	c.37G>A	p.Glu13Lys	missense_variant	1/3	1		ENSP00000177742.3
EME2	ENST00000568449	c.-145C>T		5_prime_UTR_variant	1/8	1	NM_001257370.2	ENSP00000457353.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000637 AC: 8 AN: 1255786 Hom.: 0 Cov.: 61 AF XY: 0.00000657 AC XY: 4 AN XY: 608840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000336

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000492

Gnomad4 OTH exome AF: 0.0000386

GnomAD4 genome Cov.: 35

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation deficiency 32 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 16, 2017	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 16, 2018	This variant is interpreted as a Likely Pathogenic, for Combined oxidative phosphorylation deficiency 32, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:28777931). -

Leigh syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Genetics of Mitochondrial Diseases, Imagine Institute

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.092	T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		0.99	D;D
Vest4		0.44
MutPred		0.29		Gain of ubiquitination at E13 (P = 0.0452);Gain of ubiquitination at E13 (P = 0.0452);
MVP		0.43
MPC		2.9
ClinPred		0.96	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.40
gMVP		0.62

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: rs1131692037; hg19: chr16-1823084;