11-47437918-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005055.5(RAPSN):c.*57C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,543,986 control chromosomes in the GnomAD database, including 13,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (975 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12461 hom.)
• Consequence: RAPSN NM_005055.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.44

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-47437918-G-A is Benign according to our data. Variant chr11-47437918-G-A is described in ClinVar as [Benign]. Clinvar id is 304968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47437918-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5	c.*57C>T		3_prime_UTR_variant	8/8	ENST00000298854.7
LOC124902673	XR_007062669.1	n.144+151G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7	c.*57C>T		3_prime_UTR_variant	8/8	1	NM_005055.5	P1
RAPSN	ENST00000352508.7	c.*57C>T		3_prime_UTR_variant	6/6	1
RAPSN	ENST00000524487.5	c.*57C>T		3_prime_UTR_variant	7/7	5
RAPSN	ENST00000528356.1	n.251C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16003 AN: 152130 Hom.: 975 Cov.: 32

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0880

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.0380

Gnomad SAS AF: 0.0538

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.102 AC: 15951 AN: 156074 Hom.: 1012 AF XY: 0.102 AC XY: 8365 AN XY: 82170

Gnomad AFR exome AF: 0.0654

Gnomad AMR exome AF: 0.0596

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.0380

Gnomad SAS exome AF: 0.0623

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.130 AC: 180280 AN: 1391738 Hom.: 12461 Cov.: 29 AF XY: 0.128 AC XY: 87880 AN XY: 686876

Gnomad4 AFR exome AF: 0.0617

Gnomad4 AMR exome AF: 0.0631

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.0266

Gnomad4 SAS exome AF: 0.0641

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.105 AC: 16005 AN: 152248 Hom.: 975 Cov.: 32 AF XY: 0.103 AC XY: 7650 AN XY: 74438

Gnomad4 AFR AF: 0.0637

Gnomad4 AMR AF: 0.0878

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.0380

Gnomad4 SAS AF: 0.0540

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.101

Alfa AF: 0.120 Hom.: 214

Bravo AF: 0.102

Asia WGS AF: 0.0600 AC: 207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Fetal akinesia deformation sequence 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2018

- -

Fetal akinesia deformation sequence 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.18
Dann	Benign	0.45

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: rs45617144; hg19: chr11-47459469; COSMIC: COSV54084131; COSMIC: COSV54084131;