chr3-39411706-C-T

Position:

• chr3-39411706-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_002295.6(RPSA):​c.556C>T​(p.Arg186Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPSA NM_002295.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.87

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 (HGNC:):

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, 0.819
• PP5: Variant 3-39411706-C-T is Pathogenic according to our data. Variant chr3-39411706-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 64675.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPSA	NM_002295.6	c.556C>T	p.Arg186Cys	missense_variant	5/7	ENST00000301821.11	NP_002286.2
RPSA	NM_001304288.2	c.571C>T	p.Arg191Cys	missense_variant	5/7		NP_001291217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPSA	ENST00000301821.11	c.556C>T	p.Arg186Cys	missense_variant	5/7	1	NM_002295.6	ENSP00000346067.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449640 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 721608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2023

Published functional studies demonstrate a damaging effect on protein expression (Bolze et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22560297, 20846672, 23579497) -

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	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;.;T
Eigen	Benign	0.081
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.83	L;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Uncertain	0.35
Sift	Benign	0.049	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.73
MutPred		0.73		Loss of MoRF binding (P = 0.0214);Loss of MoRF binding (P = 0.0214);.;
MVP		0.93
MPC		1.8
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.72
gMVP		0.96

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: rs397514761; hg19: chr3-39453197;