chr6-34421793-G-A

Variant names:

• chr6-34421793-G-A
• rs267607022
• NM_001014.5:c.337C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001014.5(RPS10):​c.337C>T​(p.Arg113*) variant causes a stop gained change. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RPS10 NM_001014.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.59
• Publications: 5 publications found

Genes affected

RPS10 (HGNC:10383): (ribosomal protein S10) 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 S10E family of ribosomal proteins. It is located in the cytoplasm. Variable expression of this gene in colorectal cancers compared to adjacent normal tissues has been observed, although no correlation between the level of expression and the severity of the disease has been found. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternate splicing results in multiple transcript variants that encode the same protein. Naturally occurring read-through transcription occurs between this locus and the neighboring locus NUDT3 (nudix (nucleoside diphosphate linked moiety X)-type motif 3).[provided by RefSeq, Feb 2011]

RPS10-NUDT3 (HGNC:49181): (RPS10-NUDT3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring RPS10 (ribosomal protein S10) and NUDT3 (nudix (nucleoside diphosphate linked moiety X)-type motif 3) genes on chromosome 6. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-34421793-G-A is Pathogenic according to our data. Variant chr6-34421793-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS10	NM_001014.5	c.337C>T	p.Arg113*	stop_gained	Exon 4 of 6	ENST00000648437.1	NP_001005.1
RPS10-NUDT3	NM_001202470.3	c.337C>T	p.Arg113*	stop_gained	Exon 4 of 9		NP_001189399.1
RPS10	NM_001203245.3	c.337C>T	p.Arg113*	stop_gained	Exon 4 of 6		NP_001190174.1
RPS10	NM_001204091.2	c.337C>T	p.Arg113*	stop_gained	Exon 4 of 6		NP_001191020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS10	ENST00000648437.1	c.337C>T	p.Arg113*	stop_gained	Exon 4 of 6		NM_001014.5	ENSP00000497917.1
RPS10-NUDT3	ENST00000639725.1	c.337C>T	p.Arg113*	stop_gained	Exon 4 of 9	5		ENSP00000492441.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia Pathogenic:2

Jan 14, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R113* pathogenic mutation (also known as c.337C>T), located in coding exon 3 of the RPS10 gene, results from a C to T substitution at nucleotide position 337. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation was identified in multiple individuals with Diamond-Blackfan anemia (Doherty L et al. Am. J. Hum. Genet., 2010 Feb;86:222-8; Gerrard G et al. Br. J. Haematol., 2013 Aug;162:530-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Oct 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6187). This premature translational stop signal has been observed in individual(s) with Diamond-Blackfan anemia (PMID: 20116044). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg113*) in the RPS10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPS10 are known to be pathogenic (PMID: 20116044, 23718193). -

Diamond-Blackfan anemia 9 Pathogenic:1

Aug 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		5.6
Vest4		0.96, 0.97
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs267607022; hg19: chr6-34389570; COSMIC: COSV58243116; COSMIC: COSV58243116;