3-39411688-C-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_002295.6(RPSA):​c.538C>T​(p.Arg180Trp) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPSA NM_002295.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.571

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• 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-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• PP5: Variant 3-39411688-C-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPSA	NM_002295.6	c.538C>T	p.Arg180Trp	missense_variant	Exon 5 of 7	ENST00000301821.11	NP_002286.2
RPSA	NM_001304288.2	c.553C>T	p.Arg185Trp	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>T	p.Arg180Trp	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:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 15, 2023

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. This variant disrupts the p.Arg180 amino acid residue in RPSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23579497). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change alters RPSA gene expression (PMID: 23579497). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RPSA protein function. ClinVar contains an entry for this variant (Variation ID: 64674). This missense change has been observed in individual(s) with isolated congenital asplenia (PMID: 23579497). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 180 of the RPSA protein (p.Arg180Trp). -

Familial isolated congenital asplenia Pathogenic:1

May 24, 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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;T
Eigen	Benign	-0.010
Eigen_PC	Benign	-0.0071
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.036	D;D;D
Sift4G	Benign	0.072	T;T;T
Polyphen		0.48	P;P;.
Vest4		0.91
MutPred		0.69		Gain of catalytic residue at L178 (P = 0.0042);Gain of catalytic residue at L178 (P = 0.0042);.;
MVP		0.85
MPC		2.3
ClinPred		0.95	D
GERP RS		2.6
Varity_R		0.77
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs397514760; hg19: chr3-39453179;