chr2-3575351-G-T

Variant names:

• chr2-3575351-G-T
• rs1064796859
• ENST00000462576.5:c.-259G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 PM2 PP5_Moderate

The NM_001011.4(RPS7):​c.-19+1G>T variant causes a splice donor, intron 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 Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004250925: Studies have shown that this variant alters RPS7 gene expression (PMID:36057918). Studies have shown that this variant results in the activation of cryptic splice sites and partial retention of the non-coding region in multiple RNA products, and produces a non-functional protein and/or introduces a premature termination codon (PMID:36057918).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS7 NM_001011.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.18
• Publications: 1 publications found

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]

RPS7 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 8

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124907726 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004250925: Studies have shown that this variant alters RPS7 gene expression (PMID: 36057918). Studies have shown that this variant results in the activation of cryptic splice sites and partial retention of the non-coding region in multiple RNA products, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 36057918).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-3575351-G-T is Pathogenic according to our data. Variant chr2-3575351-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2697321.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001011.4. 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
	RPS7	NM_001011.4	MANE Select	c.-19+1G>T		splice_donor intron	N/A	NP_001002.1	P62081

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS7	ENST00000462576.5	TSL:1	c.-259G>T		5_prime_UTR	Exon 1 of 6	ENSP00000495273.1	P62081
	RPS7	ENST00000645674.2	MANE Select	c.-19+1G>T		splice_donor intron	N/A	ENSP00000496757.1	P62081
	RPS7	ENST00000403564.5	TSL:2	c.-116G>T		5_prime_UTR	Exon 1 of 7	ENSP00000385018.1	P62081

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Diamond-Blackfan anemia 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	28
DANN	Benign	0.86
PhyloP100		2.2
PromoterAI		-0.63	Under-expression
Mutation Taster		=57/243	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		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

Other links and lift over

dbSNP: rs1064796859; hg19: chr2-3622941;