3-39408633-C-A

Position:

• chr3-39408633-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_002295.6(RPSA):​c.161C>A​(p.Thr54Asn) variant causes a missense change involving the alteration of a 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. T54S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPSA NM_002295.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.61

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RPSA. . Gene score misZ 2.4182 (greater than the threshold 3.09). Trascript score misZ 3.3111 (greater than threshold 3.09). GenCC has associacion of gene with familial isolated congenital asplenia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 3-39408633-C-A is Pathogenic according to our data. Variant chr3-39408633-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 64676.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPSA	NM_002295.6	c.161C>A	p.Thr54Asn	missense_variant	3/7	ENST00000301821.11
RPSA	NM_001304288.2	c.161C>A	p.Thr54Asn	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPSA	ENST00000301821.11	c.161C>A	p.Thr54Asn	missense_variant	3/7	1	NM_002295.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.;T;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.8	H;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	D;D;D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		0.15	B;B;.;.
Vest4		0.97
MutPred		0.83		Gain of MoRF binding (P = 0.1292);Gain of MoRF binding (P = 0.1292);Gain of MoRF binding (P = 0.1292);Gain of MoRF binding (P = 0.1292);
MVP		0.70
MPC		2.6
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.93
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514762; hg19: chr3-39450124;