4-151103016-A-T

Variant names:

• chr4-151103016-A-T
• rs1358218351
• NM_001006.5:c.500A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001006.5(RPS3A):​c.500A>T​(p.Lys167Met) 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPS3A NM_001006.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.19
• Publications: 0 publications found

Genes affected

RPS3A (HGNC:10421): (ribosomal protein S3A) 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 S3AE family of ribosomal proteins. It is located in the cytoplasm. Disruption of the gene encoding rat ribosomal protein S3a, also named v-fos transformation effector protein, in v-fos-transformed rat cells results in reversion of the transformed phenotype. This gene is co-transcribed with the U73A and U73B small nucleolar RNA genes, which are located in its fourth and third introns, respectively. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

SH3D19 (HGNC:30418): (SH3 domain containing 19) This gene encodes a multiple SH3 domain-containing protein, which interacts with other proteins, such as EBP and members of ADAM family, via the SH3 domains. This protein may be involved in suppression of Ras-induced cellular transformation and Ras-mediated activation of ELK1 by EBP, and regulation of ADAM proteins in the signaling of EGFR-ligand shedding. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001006.5. 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
	RPS3A	NM_001006.5	MANE Select	c.500A>T	p.Lys167Met	missense	Exon 4 of 6	NP_000997.1	P61247
	RPS3A	NM_001267699.2		c.*135A>T		3_prime_UTR	Exon 3 of 3	NP_001254628.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS3A	ENST00000274065.9	TSL:1 MANE Select	c.500A>T	p.Lys167Met	missense	Exon 4 of 6	ENSP00000346050.3	P61247
	RPS3A	ENST00000507485.1	TSL:1	n.337A>T		non_coding_transcript_exon	Exon 3 of 3
	RPS3A	ENST00000913221.1		c.500A>T	p.Lys167Met	missense	Exon 4 of 6	ENSP00000583280.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 239224 AF XY: 0.00000767

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000276 AC: 4 AN: 1449214 Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3 AN XY: 721360

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

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111702

Other (OTH) AF: 0.00 AC: 0 AN: 60298

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000431883), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.010	D
Polyphen		0.22	B
Vest4		0.83
MutPred		0.55		Loss of methylation at K166 (P = 0.038)
MVP		0.72
MPC		2.2
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.88
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs1358218351; hg19: chr4-152024168;