2-3575351-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PM2 PP3_Strong PP5_Moderate

The NM_001011.4(RPS7):c.-19+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS7 NM_001011.4 splice_donor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.18

Genes affected

RPS7 (HGNC:10440): (ribosomal protein S7) 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 S7E family of ribosomal proteins. It is located in the cytoplasm. 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-3575351-G-A is Pathogenic according to our data. Variant chr2-3575351-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 975849.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS7	NM_001011.4	c.-19+1G>A		splice_donor_variant		ENST00000645674.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS7	ENST00000645674.2	c.-19+1G>A		splice_donor_variant			NM_001011.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia 8 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous c.-19+1G>A variant in RPS7 was identified by our study in one individual with Diamond-Blackfan anemia. The c.-19+1G>A variant in RPS7 has not been previously reported in individuals with Diamond-Blackfan anemia 8. This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 975849) and has been interpreted as pathogenic by the Stanford Medicine Clinical Genomics Program. This variant was found de novo in one individual with confirmed paternity and maternity (ClinVar Variation ID: 975849). A different nucleotide change at the same site (i.e., the 5’-UTR splice-site of the RPS7 first exon), c.-19+1G>T (PMID: 36057918) has been previously reported pathogenic, and the variant being assessed here, c.-19+1G>A, is predicted by SpliceAI to have a similar effect on splicing. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Heterozygous loss of function of the RPS7 gene is an established disease mechanism in Diamond-Blackfan anemia 8. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Diamond-Blackfan anemia 8. ACMG/AMP Criteria applied: PVS1_Strong, PS1_Supporting, PS2_Moderate, PM2_Supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Program, Stanford Medicine	Dec 30, 2019	The c.-19+1G>A variant in the RPS7 gene was identified de novo in this individual, but has not been previously reported in association with disease and was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant alters the canonical donor splice site in intron 1, which is predicted to result in abnormal gene splicing. Heterozygous loss of function is an established mechanism of disease for the RPS7 gene. Notably, different nucleotide changes (c.-19+1G>C, c.- 19+1G>T, c.-19+2T>C) disrupting the same canonical splice site have been previously reported (Smetanina et al., 2015; van Dooijeweert et al., 2018). These reported disease-causing variant are expected to result in a similar disruption to protein function as c.-19+1G>A. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.-19+1G>A variant as pathogenic for autosomal dominant Diamond-Blackfan anemia based on the information above. [ACMG evidence codes used: PVS1_Strong; PS2; PM2] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Pathogenic	28
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: 3
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064796859; hg19: chr2-3622941;