rs397514760

Variant names:

• chr3-39411688-C-G
• rs397514760
• NM_002295.6:c.538C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-39411688-C-G
• chr3-39411688-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_002295.6(RPSA):​c.538C>G​(p.Arg180Gly) variant causes a missense change involving the alteration of a non-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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPSA NM_002295.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.571
• Publications: 6 publications found

Genes affected

RPSA (HGNC:6502): (ribosomal protein SA) Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Many of the effects of laminin are mediated through interactions with cell surface receptors. These receptors include members of the integrin family, as well as non-integrin laminin-binding proteins. This gene encodes a high-affinity, non-integrin family, laminin receptor 1. This receptor has been variously called 67 kD laminin receptor, 37 kD laminin receptor precursor (37LRP) and p40 ribosome-associated protein. The amino acid sequence of laminin receptor 1 is highly conserved through evolution, suggesting a key biological function. It has been observed that the level of the laminin receptor transcript is higher in colon carcinoma tissue and lung cancer cell line than their normal counterparts. Also, there is a correlation between the upregulation of this polypeptide in cancer cells and their invasive and metastatic phenotype. Multiple copies of this gene exist, however, most of them are pseudogenes thought to have arisen from retropositional events. Two alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

RPSA Gene-Disease associations (from GenCC):

• familial isolated congenital asplenia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a chain 40S ribosomal protein SA (size 293) in uniprot entity RSSA_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002295.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-39411688-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 64674.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 3-39411688-C-G is Pathogenic according to our data. Variant chr3-39411688-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 64673.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPSA	NM_002295.6	c.538C>G	p.Arg180Gly	missense_variant	Exon 5 of 7	ENST00000301821.11	NP_002286.2
RPSA	NM_001304288.2	c.553C>G	p.Arg185Gly	missense_variant	Exon 5 of 7		NP_001291217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPSA	ENST00000301821.11	c.538C>G	p.Arg180Gly	missense_variant	Exon 5 of 7	1	NM_002295.6	ENSP00000346067.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial isolated congenital asplenia Pathogenic:1

May 24, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.8	M;.;.
PhyloP100		0.57
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.017	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		0.39	B;B;.
Vest4		0.96
MutPred		0.68		Loss of MoRF binding (P = 0.0298);Loss of MoRF binding (P = 0.0298);.;
MVP		0.86
MPC		2.6
ClinPred		0.97	D
GERP RS		2.6
Varity_R		0.96
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs397514760; hg19: chr3-39453179;