10-73250926-G-A

Position:

• chr10-73250926-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016065.4(MRPS16):​c.340C>T​(p.Arg114Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,461,844 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R114Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: MRPS16 NM_016065.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

Genes affected

MRPS16 (HGNC:14048): (mitochondrial ribosomal protein S16) 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 that belongs to the ribosomal protein S16P family. The encoded protein is one of the most highly conserved ribosomal proteins between mammalian and yeast mitochondria. Three pseudogenes (located at 8q21.3, 20q13.32, 22q12-q13.1) for this gene have been described. [provided by RefSeq, Jul 2008]

DNAJC9-AS1 (HGNC:31432): (DNAJC9 and MRPS16 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36494786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPS16	NM_016065.4	c.340C>T	p.Arg114Trp	missense_variant	3/3	ENST00000372945.8
DNAJC9-AS1	NR_038373.1	n.175+2476G>A		intron_variant, non_coding_transcript_variant
MRPS16	XM_047425263.1	c.334C>T	p.Arg112Trp	missense_variant	3/3
MRPS16	NM_001410935.1	c.274+837C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPS16	ENST00000372945.8	c.340C>T	p.Arg114Trp	missense_variant	3/3	1	NM_016065.4	P1
DNAJC9-AS1	ENST00000440197.2	n.182+2476G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251474 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461844 Hom.: 0 Cov.: 30 AF XY: 0.0000316 AC XY: 23 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.340C>T (p.R114W) alteration is located in exon 3 (coding exon 3) of the MRPS16 gene. This alteration results from a C to T substitution at nucleotide position 340, causing the arginine (R) at amino acid position 114 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.48		Loss of disorder (P = 8e-04);
MVP		0.70
MPC		0.59
ClinPred		0.52	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.62

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: rs781162258; hg19: chr10-75010684;