chr16-1772946-C-G

Position:

• chr16-1772946-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_023936.2(MRPS34):​c.174G>C​(p.Val58=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,445,350 control chromosomes in the GnomAD database, including 12,579 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (997 hom., cov: 35)
  • Exomes 𝑓: 0.13 (11582 hom.)
• Consequence: MRPS34 NM_023936.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.73

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 16-1772946-C-G is Benign according to our data. Variant chr16-1772946-C-G is described in ClinVar as [Benign]. Clinvar id is 1275184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPS34	NM_023936.2	c.174G>C	p.Val58=	synonymous_variant	1/3	ENST00000397375.7
EME2	NM_001257370.2	c.-282C>G		5_prime_UTR_variant	1/8	ENST00000568449.7
MRPS34	NM_001300900.2	c.174G>C	p.Val58=	synonymous_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPS34	ENST00000397375.7	c.174G>C	p.Val58=	synonymous_variant	1/3	1	NM_023936.2	P1
MRPS34	ENST00000177742.7	c.174G>C	p.Val58=	synonymous_variant	1/3	1
EME2	ENST00000568449.7	c.-282C>G		5_prime_UTR_variant	1/8	1	NM_001257370.2	P1

Frequencies

GnomAD3 genomes AF: 0.0967 AC: 14718 AN: 152206 Hom.: 997 Cov.: 35

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0996

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0482

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.0935 AC: 4511 AN: 48254 Hom.: 285 AF XY: 0.0939 AC XY: 2504 AN XY: 26676

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.0782

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0423

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.127 AC: 164706 AN: 1293028 Hom.: 11582 Cov.: 67 AF XY: 0.126 AC XY: 79399 AN XY: 631970

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.0789

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.000190

Gnomad4 SAS exome AF: 0.0508

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.0966 AC: 14708 AN: 152322 Hom.: 997 Cov.: 35 AF XY: 0.0940 AC XY: 7003 AN XY: 74478

Gnomad4 AFR AF: 0.0259

Gnomad4 AMR AF: 0.0995

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0478

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.110

Alfa AF: 0.110 Hom.: 139

Bravo AF: 0.0933

Asia WGS AF: 0.0250 AC: 87 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

MRPS34-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs1076695; hg19: chr16-1822947; COSMIC: COSV51602155; COSMIC: COSV51602155;