16-1772974-C-T

Variant names:

• chr16-1772974-C-T
• rs990190809
• NM_001257370.2:c.-254C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001257370.2(EME2):​c.-254C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000772 in 1,295,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: EME2 NM_001257370.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.389
• Publications: 0 publications found

Genes affected

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]

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]

MRPS34 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 32

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13445449).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257370.2. 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
	EME2	NM_001257370.2	MANE Select	c.-254C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001244299.1	A4GXA9-1
	MRPS34	NM_023936.2	MANE Select	c.146G>A	p.Arg49Gln	missense	Exon 1 of 3	NP_076425.1	P82930
	EME2	NM_001257370.2	MANE Select	c.-254C>T		5_prime_UTR	Exon 1 of 8	NP_001244299.1	A4GXA9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EME2	ENST00000568449.7	TSL:1 MANE Select	c.-254C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000457353.1	A4GXA9-1
	MRPS34	ENST00000397375.7	TSL:1 MANE Select	c.146G>A	p.Arg49Gln	missense	Exon 1 of 3	ENSP00000380531.3	P82930
	MRPS34	ENST00000177742.7	TSL:1	c.146G>A	p.Arg49Gln	missense	Exon 1 of 3	ENSP00000177742.3	C9JJ19

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.0000190 AC: 1 AN: 52590 AF XY: 0.0000339

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000574

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1295346 Hom.: 0 Cov.: 63 AF XY: 0.00000158 AC XY: 1 AN XY: 633312

African (AFR) AF: 0.00 AC: 0 AN: 25246

American (AMR) AF: 0.00 AC: 0 AN: 20282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19388

East Asian (EAS) AF: 0.00 AC: 0 AN: 30732

South Asian (SAS) AF: 0.00 AC: 0 AN: 65810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5048

European-Non Finnish (NFE) AF: 9.66e-7 AC: 1 AN: 1034688

Other (OTH) AF: 0.00 AC: 0 AN: 53416

GnomAD4 genome Cov.: 35

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.39
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.021
Sift	Benign	0.048	D
Sift4G	Benign	0.14	T
Polyphen		0.12	B
Vest4		0.14
MutPred		0.33		Loss of methylation at R49 (P = 0.0216)
MVP		0.28
MPC		1.7
ClinPred		0.075	T
GERP RS		0.58
PromoterAI		-0.065	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.039
gMVP		0.52

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: rs990190809; hg19: chr16-1822975;