16-1772844-C-T

Variant names:

• chr16-1772844-C-T
• rs1056386574
• NM_001257370.2:c.-384C>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.-384C>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 0.000000774 in 1,291,364 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: 7.7e-7 (0 hom.)
• Consequence: EME2 NM_001257370.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.452
• 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 (BayesDel_noAF=-0.38).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EME2	NM_001257370.2	c.-384C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	ENST00000568449.7	NP_001244299.1
MRPS34	NM_023936.2	c.276G>A	p.Pro92Pro	synonymous_variant	Exon 1 of 3	ENST00000397375.7	NP_076425.1
EME2	NM_001257370.2	c.-384C>T		5_prime_UTR_variant	Exon 1 of 8	ENST00000568449.7	NP_001244299.1
MRPS34	NM_001300900.2	c.276G>A	p.Pro92Pro	synonymous_variant	Exon 1 of 3		NP_001287829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EME2	ENST00000568449.7	c.-384C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	1	NM_001257370.2	ENSP00000457353.1
MRPS34	ENST00000397375.7	c.276G>A	p.Pro92Pro	synonymous_variant	Exon 1 of 3	1	NM_023936.2	ENSP00000380531.3
EME2	ENST00000568449.7	c.-384C>T		5_prime_UTR_variant	Exon 1 of 8	1	NM_001257370.2	ENSP00000457353.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.74e-7 AC: 1 AN: 1291364 Hom.: 0 Cov.: 61 AF XY: 0.00000159 AC XY: 1 AN XY: 627402

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28490

American (AMR) AF: 0.00 AC: 0 AN: 21150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19090

East Asian (EAS) AF: 0.00 AC: 0 AN: 34508

South Asian (SAS) AF: 0.00 AC: 0 AN: 64880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4002

European-Non Finnish (NFE) AF: 9.66e-7 AC: 1 AN: 1035378

Other (OTH) AF: 0.00 AC: 0 AN: 53628

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		0.45
PromoterAI		0.00070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1056386574; hg19: chr16-1822845;