11-47437918-G-A

Variant names:

• chr11-47437918-G-A
• rs45617144
• NM_005055.5:c.*57C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 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:6
• Conservation: PhyloP100: -1.44
• Publications: 9 publications found

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]

RAPSN Gene-Disease associations (from GenCC):

• fetal akinesia deformation sequence 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• neuromuscular disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• congenital myasthenic syndrome 11

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124902673 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.218).
• 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.
• 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 rank	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.*57C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000298854.7	NP_005046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7	c.*57C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_005055.5	ENSP00000298854.2
RAPSN	ENST00000352508.7	c.*57C>T		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000298853.3
RAPSN	ENST00000528356.1	n.251C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3
RAPSN	ENST00000524487.5	c.*57C>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000435551.2

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

GnomAD2 exomes AF: 0.102 AC: 15951 AN: 156074 AF XY: 0.102

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 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

African (AFR) AF: 0.0617 AC: 1939 AN: 31432

American (AMR) AF: 0.0631 AC: 2251 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3653 AN: 25148

East Asian (EAS) AF: 0.0266 AC: 949 AN: 35682

South Asian (SAS) AF: 0.0641 AC: 5072 AN: 79078

European-Finnish (FIN) AF: 0.134 AC: 6557 AN: 48944

Middle Eastern (MID) AF: 0.130 AC: 710 AN: 5478

European-Non Finnish (NFE) AF: 0.142 AC: 152159 AN: 1072532

Other (OTH) AF: 0.121 AC: 6990 AN: 57754

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

African (AFR) AF: 0.0637 AC: 2650 AN: 41576

American (AMR) AF: 0.0878 AC: 1343 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 500 AN: 3468

East Asian (EAS) AF: 0.0380 AC: 197 AN: 5178

South Asian (SAS) AF: 0.0540 AC: 261 AN: 4830

European-Finnish (FIN) AF: 0.127 AC: 1353 AN: 10612

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9410 AN: 67980

Other (OTH) AF: 0.101 AC: 213 AN: 2106

Alfa AF: 0.125 Hom.: 1627

Bravo AF: 0.102

Asia WGS AF: 0.0600 AC: 207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 11 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fetal akinesia deformation sequence 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Fetal akinesia deformation sequence 2 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.18
DANN	Benign	0.45
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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