rs121909257

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The ENST00000298854.7(RAPSN):​c.566C>T​(p.Ala189Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,878 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. A189G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

RAPSN
ENST00000298854.7 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.52
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a repeat TPR 4 (size 33) in uniprot entity RAPSN_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in ENST00000298854.7
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAPSNNM_005055.5 linkuse as main transcriptc.566C>T p.Ala189Val missense_variant 3/8 ENST00000298854.7 NP_005046.2
LOC124902673XR_007062669.1 linkuse as main transcriptn.145-4547G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAPSNENST00000298854.7 linkuse as main transcriptc.566C>T p.Ala189Val missense_variant 3/81 NM_005055.5 ENSP00000298854 P1Q13702-1
RAPSNENST00000352508.7 linkuse as main transcriptc.566C>T p.Ala189Val missense_variant 3/61 ENSP00000298853 Q13702-2
RAPSNENST00000529341.1 linkuse as main transcriptc.566C>T p.Ala189Val missense_variant 3/51 ENSP00000431732
RAPSNENST00000524487.5 linkuse as main transcriptc.532-859C>T intron_variant 5 ENSP00000435551

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251458
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461878
Hom.:
0
Cov.:
34
AF XY:
0.00000550
AC XY:
4
AN XY:
727238
show subpopulations
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:
0.00000899
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000307
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Fetal akinesia deformation sequence 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2008- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 04, 2024Variant summary: RAPSN c.566C>T (p.Ala189Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251458 control chromosomes (gnomAD). c.566C>T has been reported in the literature in the compound heterozygous state in two siblings born at term affected with Fetal Akinesia Deformation Sequence (FADS), from a family where the variant segregated with disease and there was a history of preterm abortion (Michalk_2008). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 18252226). ClinVar contains an entry for this variant (Variation ID: 8059). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.38
T;.;.
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.076
D
MetaRNN
Pathogenic
0.94
D;D;D
MetaSVM
Uncertain
0.19
D
MutationAssessor
Benign
0.90
L;L;.
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-3.1
D;D;D
REVEL
Uncertain
0.58
Sift
Uncertain
0.0030
D;D;D
Sift4G
Uncertain
0.013
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.90
MutPred
0.85
Gain of catalytic residue at A189 (P = 0.0112);Gain of catalytic residue at A189 (P = 0.0112);Gain of catalytic residue at A189 (P = 0.0112);
MVP
0.91
MPC
0.63
ClinPred
0.96
D
GERP RS
5.1
Varity_R
0.66
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121909257; hg19: chr11-47464332; COSMIC: COSV100100029; COSMIC: COSV100100029; API