rs116840811

Variant names:

• chr15-82540427-A-C
• rs116840811
• NM_001021.6:c.2T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001021.6(RPS17):​c.2T>G​(p.Met1?) variant causes a start lost, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS17 NM_001021.6 start_lost, splice_region
• Scores: Splicing: ADA: 0.009343
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.19
• Publications: 6 publications found

Genes affected

RPS17 (HGNC:10397): (ribosomal protein S17) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four 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 S17E family of ribosomal proteins and is located in the cytoplasm. Mutations in this gene cause Diamond-Blackfan anemia 4. Alternative splicing of this gene results in multiple transcript variants. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Apr 2014]

RPS17 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 4

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000260836 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-82540427-A-C is Pathogenic according to our data. Variant chr15-82540427-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12999.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001021.6. 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
	RPS17	NM_001021.6	MANE Select	c.2T>G	p.Met1?	start_lost splice_region	Exon 1 of 5	NP_001012.1
	RPS17	NR_111943.2		n.31T>G		non_coding_transcript_exon	Exon 1 of 4
	RPS17	NR_111944.3		n.31T>G		splice_region non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS17	ENST00000647841.1	MANE Select	c.2T>G	p.Met1?	start_lost splice_region	Exon 1 of 5	ENSP00000498019.1
	ENSG00000260836	ENST00000562833.2	TSL:3	c.1351-295T>G		intron	N/A	ENSP00000454786.2
	RPS17	ENST00000560229.6	TSL:1	n.31T>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Diamond-Blackfan anemia (1)
1	-	-	Diamond-Blackfan anemia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.15	T
PhyloP100		4.2
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.75
MutPred		0.94		Gain of methylation at M1 (P = 0.0013)
MVP		0.88
ClinPred		0.99	D
GERP RS		3.3
PromoterAI		-0.36	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.99
gMVP		0.69
Mutation Taster		=2/198	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0093
dbscSNV1_RF	Benign	0.088
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

dbSNP: rs116840811; hg19: chr15-83209178;