11-47437768-G-T

Variant names:

• chr11-47437768-G-T
• rs73459751
• NM_005055.5:c.*207C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005055.5(RAPSN):​c.*207C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 692,626 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (40 hom.)
• Consequence: RAPSN NM_005055.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.802
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 11-47437768-G-T is Benign according to our data. Variant chr11-47437768-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 304966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0174 (2651/152284) while in subpopulation AFR AF = 0.0486 (2021/41542). AF 95% confidence interval is 0.0469. There are 47 homozygotes in GnomAd4. There are 1296 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.*207C>A		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.*207C>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_005055.5	ENSP00000298854.2
RAPSN	ENST00000352508.7	c.*207C>A		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000298853.3
RAPSN	ENST00000528356.1	n.401C>A		non_coding_transcript_exon_variant	Exon 2 of 2	3
RAPSN	ENST00000524487.5	c.*207C>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000435551.2

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2647 AN: 152166 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00517

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00621 AC: 692 AN: 111486 AF XY: 0.00521

Gnomad AFR exome AF: 0.0486

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00310

Gnomad EAS exome AF: 0.000103

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00587 AC: 3173 AN: 540342 Hom.: 40 Cov.: 6 AF XY: 0.00542 AC XY: 1565 AN XY: 288502

African (AFR) AF: 0.0442 AC: 647 AN: 14654

American (AMR) AF: 0.00424 AC: 119 AN: 28058

Ashkenazi Jewish (ASJ) AF: 0.00348 AC: 61 AN: 17522

East Asian (EAS) AF: 0.0000324 AC: 1 AN: 30894

South Asian (SAS) AF: 0.000647 AC: 37 AN: 57210

European-Finnish (FIN) AF: 0.0120 AC: 367 AN: 30466

Middle Eastern (MID) AF: 0.00939 AC: 36 AN: 3834

European-Non Finnish (NFE) AF: 0.00515 AC: 1692 AN: 328470

Other (OTH) AF: 0.00729 AC: 213 AN: 29234

GnomAD4 genome AF: 0.0174 AC: 2651 AN: 152284 Hom.: 47 Cov.: 32 AF XY: 0.0174 AC XY: 1296 AN XY: 74468

African (AFR) AF: 0.0486 AC: 2021 AN: 41542

American (AMR) AF: 0.00510 AC: 78 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00518 AC: 352 AN: 68016

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0146 Hom.: 7

Bravo AF: 0.0175

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Fetal akinesia deformation sequence 1 Benign:1

Jan 12, 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. -

Congenital myasthenic syndrome 11 Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		0.80
Mutation Taster		=98/2	polymorphism

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: rs73459751; hg19: chr11-47459319;