NM_002295.6:c.161C>G

Variant names:

• chr3-39408633-C-G
• rs397514762
• NM_002295.6:c.161C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_002295.6(RPSA):​c.161C>G​(p.Thr54Ser) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T54N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPSA NM_002295.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61
• Publications: 3 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]

SNORA6 (HGNC:32591): (small nucleolar RNA, H/ACA box 6)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-39408633-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 64676.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002295.6. 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
	RPSA	NM_002295.6	MANE Select	c.161C>G	p.Thr54Ser	missense	Exon 3 of 7	NP_002286.2
	RPSA	NM_001304288.2		c.161C>G	p.Thr54Ser	missense	Exon 3 of 7	NP_001291217.1	A0A0C4DG17
	SNORA6	NR_002325.1		n.*94C>G		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPSA	ENST00000301821.11	TSL:1 MANE Select	c.161C>G	p.Thr54Ser	missense	Exon 3 of 7	ENSP00000346067.4	P08865
	RPSA	ENST00000443003.2	TSL:1	c.161C>G	p.Thr54Ser	missense	Exon 3 of 7	ENSP00000389351.1	A0A0C4DG17
	RPSA	ENST00000922536.1		c.161C>G	p.Thr54Ser	missense	Exon 3 of 7	ENSP00000592595.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.029	D
Polyphen		0.14	B
Vest4		0.90
MutPred		0.81		Gain of MoRF binding (P = 0.1131)
MVP		0.73
MPC		1.9
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.92
gMVP		0.88
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs397514762; hg19: chr3-39450124;