16-1772825-G-C

Variant names:

• chr16-1772825-G-C
• rs753841145
• NM_023936.2:c.295C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_023936.2(MRPS34):​c.295C>G​(p.Arg99Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000232 in 1,292,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: MRPS34 NM_023936.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.44

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35603285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS34	NM_023936.2	c.295C>G	p.Arg99Gly	missense_variant	Exon 1 of 3	ENST00000397375.7	NP_076425.1
EME2	NM_001257370.2	c.-403G>C		5_prime_UTR_variant	Exon 1 of 8	ENST00000568449.7	NP_001244299.1
MRPS34	NM_001300900.2	c.295C>G	p.Arg99Gly	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.295C>G	p.Arg99Gly	missense_variant	Exon 1 of 3	1	NM_023936.2	ENSP00000380531.3
MRPS34	ENST00000177742.7	c.295C>G	p.Arg99Gly	missense_variant	Exon 1 of 3	1		ENSP00000177742.3
EME2	ENST00000568449	c.-403G>C		5_prime_UTR_variant	Exon 1 of 8	1	NM_001257370.2	ENSP00000457353.1
MRPS34	ENST00000569585.1	n.-127C>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.0000157 AC: 1 AN: 63734 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 32572

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000387

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000232 AC: 3 AN: 1292424 Hom.: 0 Cov.: 63 AF XY: 0.00000159 AC XY: 1 AN XY: 627840

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: 0.00000290

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.90	P;P
Vest4		0.42
MutPred		0.50		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP		0.19
MPC		2.8
ClinPred		0.89	D
GERP RS		3.7
Varity_R		0.51
gMVP		0.87

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: rs753841145; hg19: chr16-1822826;