17-28720857-A-C

Variant names:

• chr17-28720857-A-C
• rs61738395
• NM_000984.6:c.176A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000984.6(RPL23A):​c.176A>C​(p.Lys59Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RPL23A NM_000984.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.16

Genes affected

RPL23A (HGNC:10317): (ribosomal protein L23a) 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 60S subunit. The protein belongs to the L23P family of ribosomal proteins. It is located in the cytoplasm. The protein may be one of the target molecules involved in mediating growth inhibition by interferon. In yeast, the corresponding protein binds to a specific site on the 26S rRNA. This gene is co-transcribed with the U42A, U42B, U101A, and U101B small nucleolar RNA genes, which are located in its third, first, second, and fourth introns, respectively. 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]

SNORD42B (HGNC:10181): (small nucleolar RNA, C/D box 42B)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL23A	NM_000984.6	c.176A>C	p.Lys59Thr	missense_variant	Exon 2 of 5	ENST00000422514.7	NP_000975.2
SNORD42B	NR_000013.1	n.*241A>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL23A	ENST00000422514.7	c.176A>C	p.Lys59Thr	missense_variant	Exon 2 of 5	1	NM_000984.6	ENSP00000389103.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.176A>C (p.K59T) alteration is located in exon 2 (coding exon 2) of the RPL23A gene. This alteration results from a A to C substitution at nucleotide position 176, causing the lysine (K) at amino acid position 59 to be replaced by a threonine (T). 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	0.82
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.4	M;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.1	D;D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.016	D;D;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.64	P;.;.
Vest4		0.70
MutPred		0.48		Loss of methylation at K59 (P = 0.0011);.;.;
MVP		0.54
MPC		1.5
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.40
gMVP		0.55

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: rs61738395; hg19: chr17-27047875;