16-1772371-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_023936.2(MRPS34):c.507C>T(p.Leu169=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,612,432 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (19 hom.)
• Consequence: MRPS34 NM_023936.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0960

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-1772371-G-A is Benign according to our data. Variant chr16-1772371-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1600465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.096 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00265 (3871/1460124) while in subpopulation MID AF= 0.0201 (116/5766). AF 95% confidence interval is 0.0171. There are 19 homozygotes in gnomad4_exome. There are 1956 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPS34	NM_023936.2	c.507C>T	p.Leu169=	synonymous_variant	3/3	ENST00000397375.7
MRPS34	NM_001300900.2	c.528C>T	p.Leu176=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPS34	ENST00000397375.7	c.507C>T	p.Leu169=	synonymous_variant	3/3	1	NM_023936.2	P1
MRPS34	ENST00000177742.7	c.528C>T	p.Leu176=	synonymous_variant	3/3	1
MRPS34	ENST00000569585.1	n.238C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152190 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00392 AC: 979 AN: 249472 Hom.: 6 AF XY: 0.00425 AC XY: 576 AN XY: 135436

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00250

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00451

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.00363

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00265 AC: 3871 AN: 1460124 Hom.: 19 Cov.: 32 AF XY: 0.00269 AC XY: 1956 AN XY: 726342

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00402

Gnomad4 FIN exome AF: 0.0147

Gnomad4 NFE exome AF: 0.00212

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00280 AC: 427 AN: 152308 Hom.: 3 Cov.: 33 AF XY: 0.00357 AC XY: 266 AN XY: 74476

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MRPS34: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 16, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.4
Dann	Benign	0.90

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: rs147183681; hg19: chr16-1822372;