16-1772999-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_023936.2(MRPS34):c.121T>C(p.Leu41=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,454,120 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: MRPS34 NM_023936.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.412

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 -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 16-1772999-A-G is Benign according to our data. Variant chr16-1772999-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2042832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.412 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0012 (183/152348) while in subpopulation AFR AF= 0.00409 (170/41586). AF 95% confidence interval is 0.00359. There are 0 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPS34	NM_023936.2	c.121T>C	p.Leu41=	synonymous_variant	1/3	ENST00000397375.7
EME2	NM_001257370.2	c.-229A>G		5_prime_UTR_variant	1/8	ENST00000568449.7
MRPS34	NM_001300900.2	c.121T>C	p.Leu41=	synonymous_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPS34	ENST00000397375.7	c.121T>C	p.Leu41=	synonymous_variant	1/3	1	NM_023936.2	P1
MRPS34	ENST00000177742.7	c.121T>C	p.Leu41=	synonymous_variant	1/3	1
EME2	ENST00000568449.7	c.-229A>G		5_prime_UTR_variant	1/8	1	NM_001257370.2	P1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152232 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.0000503 AC: 3 AN: 59654 Hom.: 0 AF XY: 0.0000298 AC XY: 1 AN XY: 33598

Gnomad AFR exome AF: 0.00317

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000807 AC: 105 AN: 1301772 Hom.: 0 Cov.: 62 AF XY: 0.0000785 AC XY: 50 AN XY: 636558

Gnomad4 AFR exome AF: 0.00342

Gnomad4 AMR exome AF: 0.000141

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: 9.65e-7

Gnomad4 OTH exome AF: 0.000261

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152348 Hom.: 0 Cov.: 35 AF XY: 0.00129 AC XY: 96 AN XY: 74506

Gnomad4 AFR AF: 0.00409

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.00116

Asia WGS AF: 0.00145 AC: 5 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MRPS34-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	7.7
Dann	Benign	0.59

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: rs538094386; hg19: chr16-1823000;