chr1-44776724-A-C

Variant names:

• chr1-44776724-A-C
• NM_001012.2:c.161A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001012.2(RPS8):​c.161A>C​(p.Lys54Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. K54N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000079 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPS8 NM_001012.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.71
• Publications: 0 publications found

Genes affected

RPS8 (HGNC:10441): (ribosomal protein S8) 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 S8E family of ribosomal proteins. It is located in the cytoplasm. Increased expression of this gene in colorectal tumors and colon polyps compared to matched normal colonic mucosa has been observed. This gene is co-transcribed with the small nucleolar RNA genes U38A, U38B, U39, and U40, which are located in its fourth, fifth, first, and second 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]

SNORD46 (HGNC:10186): (small nucleolar RNA, C/D box 46)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS8	NM_001012.2	MANE Select	c.161A>C	p.Lys54Thr	missense	Exon 3 of 6	NP_001003.1	P62241
	SNORD46	NR_000024.2		n.*135A>C		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS8	ENST00000396651.8	TSL:1 MANE Select	c.161A>C	p.Lys54Thr	missense	Exon 3 of 6	ENSP00000379888.3	P62241
	RPS8	ENST00000485390.5	TSL:1	n.555A>C		non_coding_transcript_exon	Exon 2 of 5
	RPS8	ENST00000932906.1		c.161A>C	p.Lys54Thr	missense	Exon 3 of 6	ENSP00000602965.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000788 AC: 115 AN: 1460144 Hom.: 0 Cov.: 30 AF XY: 0.0000757 AC XY: 55 AN XY: 726412

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000150 AC: 5 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000909 AC: 101 AN: 1110754

Other (OTH) AF: 0.0000829 AC: 5 AN: 60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.077	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		8.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.80		Loss of methylation at K54 (P = 0.0601)
MVP		0.69
MPC		2.6
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.98
Mutation Taster		=16/84	disease causing

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

Other links and lift over

hg19: chr1-45242396;