rs200695559

chr11-47441730-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_005055.5(RAPSN):c.793G>A(p.Ala265Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,346 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A265V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.38

Genes affected

RAPSN (HGNC:9863): (receptor associated protein of the synapse) This gene encodes a member of a family of proteins that are receptor associated proteins of the synapse. The encoded protein contains a conserved cAMP-dependent protein kinase phosphorylation site, and plays a critical role in clustering and anchoring nicotinic acetylcholine receptors at synaptic sites by linking the receptors to the underlying postsynaptic cytoskeleton, possibly by direct association with actin or spectrin. Mutations in this gene may play a role in postsynaptic congenital myasthenic syndromes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Apr 2011]

LOC124902673 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 chr11-47441729-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 692283.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5	c.793G>A	p.Ala265Thr	missense_variant	5/8	ENST00000298854.7
LOC124902673	XR_007062669.1	n.144+3963C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7	c.793G>A	p.Ala265Thr	missense_variant	5/8	1	NM_005055.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454442 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 723906

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2021	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 265 of the RAPSN protein (p.Ala265Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RAPSN-related conditions. ClinVar contains an entry for this variant (Variation ID: 548027). 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 expected to disrupt RAPSN protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		1.0	D;.
Vest4		0.91
MVP		0.99
MPC		0.63
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.78
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200695559; hg19: chr11-47463282; COSMIC: COSV100100371;