16-1772890-C-T

Variant names:

• chr16-1772890-C-T
• rs1158749659
• NM_023936.2:c.230G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_023936.2(MRPS34):​c.230G>A​(p.Gly77Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,452,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: MRPS34 NM_023936.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023936.2. 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
	MRPS34	NM_023936.2	MANE Select	c.230G>A	p.Gly77Asp	missense	Exon 1 of 3	NP_076425.1	P82930
	EME2	NM_001257370.2	MANE Select	c.-338C>T		5_prime_UTR	Exon 1 of 8	NP_001244299.1	A4GXA9-1
	MRPS34	NM_001300900.2		c.230G>A	p.Gly77Asp	missense	Exon 1 of 3	NP_001287829.1	C9JJ19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS34	ENST00000397375.7	TSL:1 MANE Select	c.230G>A	p.Gly77Asp	missense	Exon 1 of 3	ENSP00000380531.3	P82930
	MRPS34	ENST00000177742.7	TSL:1	c.230G>A	p.Gly77Asp	missense	Exon 1 of 3	ENSP00000177742.3	C9JJ19
	EME2	ENST00000568449.7	TSL:1 MANE Select	c.-338C>T		5_prime_UTR	Exon 1 of 8	ENSP00000457353.1	A4GXA9-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1300406 Hom.: 0 Cov.: 63 AF XY: 0.00000315 AC XY: 2 AN XY: 635500

African (AFR) AF: 0.00 AC: 0 AN: 27098

American (AMR) AF: 0.00 AC: 0 AN: 22260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19620

East Asian (EAS) AF: 0.00 AC: 0 AN: 32860

South Asian (SAS) AF: 0.0000149 AC: 1 AN: 67066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4404

European-Non Finnish (NFE) AF: 9.60e-7 AC: 1 AN: 1041828

Other (OTH) AF: 0.00 AC: 0 AN: 54004

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 74390

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.54		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.20
MPC		3.2
ClinPred		0.99	D
GERP RS		3.7
PromoterAI		-0.079	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.81
gMVP		0.94
Mutation Taster		=6/94	disease causing

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: rs1158749659; hg19: chr16-1822891; COSMIC: COSV51599550; COSMIC: COSV51599550;