19-39435706-C-A

Position:

• chr19-39435706-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000251453.8(RPS16):​c.51G>T​(p.Lys17Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS16 ENST00000251453.8 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

Genes affected

RPS16 (HGNC:10396): (ribosomal protein S16) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S9P family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS16	NM_001020.6	c.51G>T	p.Lys17Asn	missense_variant, splice_region_variant	2/5	ENST00000251453.8	NP_001011.1
RPS16	NM_001363860.2	c.51G>T	p.Lys17Asn	missense_variant, splice_region_variant	2/4		NP_001350789.1
RPS16	NM_001321111.2	c.51G>T	p.Lys17Asn	missense_variant, splice_region_variant	2/5		NP_001308040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS16	ENST00000251453.8	c.51G>T	p.Lys17Asn	missense_variant, splice_region_variant	2/5	1	NM_001020.6	ENSP00000251453	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jan 23, 2023

The c.51G>T (p.K17N) alteration is located in exon 2 (coding exon 2) of the RPS16 gene. This alteration results from a G to T substitution at nucleotide position 51, causing the lysine (K) at amino acid position 17 to be replaced by an asparagine (N). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T;D;T
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	5.6	.;.;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.9	.;D;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	.;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.99, 0.99	.;D;D;.
Vest4		0.95
MutPred		0.79		Loss of methylation at K17 (P = 0.0124);Loss of methylation at K17 (P = 0.0124);Loss of methylation at K17 (P = 0.0124);Loss of methylation at K17 (P = 0.0124);
MVP		0.31
MPC		2.0
ClinPred		1.0	D
GERP RS		0.42
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.90
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-39926346;