10-73250218-C-CA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_016065.4(MRPS16):c.*633_*634insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 132,152 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (11 hom., cov: 27)
  • Exomes 𝑓: 0.049 (0 hom.)
• Consequence: MRPS16 NM_016065.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0840

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00535 (704/131576) while in subpopulation EAS AF= 0.0518 (236/4556). AF 95% confidence interval is 0.0464. There are 11 homozygotes in gnomad4. There are 418 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPS16	NM_016065.4	c.*633_*634insT		3_prime_UTR_variant	3/3	ENST00000372945.8
DNAJC9-AS1	NR_038373.1	n.175+1784dup		intron_variant, non_coding_transcript_variant
MRPS16	XM_047425263.1	c.*633_*634insT		3_prime_UTR_variant	3/3
MRPS16	NM_001410935.1	c.275-901_275-900insT		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPS16	ENST00000372945.8	c.*633_*634insT		3_prime_UTR_variant	3/3	1	NM_016065.4	P1
DNAJC9-AS1	ENST00000440197.2	n.182+1784dup		intron_variant, non_coding_transcript_variant		1
MRPS16	ENST00000372940.3	c.275-901_275-900insT		intron_variant		2
MRPS16	ENST00000479005.1	n.1204_1205insT		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00537 AC: 706 AN: 131526 Hom.: 11 Cov.: 27

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00119

Gnomad AMR AF: 0.00592

Gnomad ASJ AF: 0.000313

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.00591

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.00357

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00902

GnomAD4 exome AF: 0.0486 AC: 28 AN: 576 Hom.: 0 Cov.: 0 AF XY: 0.0511 AC XY: 19 AN XY: 372

Gnomad4 AMR exome AF: 0.0600

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0625

Gnomad4 SAS exome AF: 0.0294

Gnomad4 NFE exome AF: 0.0502

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00535 AC: 704 AN: 131576 Hom.: 11 Cov.: 27 AF XY: 0.00662 AC XY: 418 AN XY: 63178

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00591

Gnomad4 ASJ AF: 0.000313

Gnomad4 EAS AF: 0.0518

Gnomad4 SAS AF: 0.00593

Gnomad4 FIN AF: 0.0238

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.00895

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs555061429; hg19: chr10-75009976;