11-47437768-G-T

Position:

• chr11-47437768-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5	c.*207C>A		3_prime_UTR_variant	8/8	ENST00000298854.7
LOC124902673	XR_007062669.1	n.144+1G>T		splice_donor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7	c.*207C>A		3_prime_UTR_variant	8/8	1	NM_005055.5	P1
RAPSN	ENST00000352508.7	c.*207C>A		3_prime_UTR_variant	6/6	1
RAPSN	ENST00000524487.5	c.*207C>A		3_prime_UTR_variant	7/7	5
RAPSN	ENST00000528356.1	n.401C>A		non_coding_transcript_exon_variant	2/2	3

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

GnomAD3 exomes AF: 0.00621 AC: 692 AN: 111486 Hom.: 13 AF XY: 0.00521 AC XY: 313 AN XY: 60134

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 SAS exome AF: 0.000643

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

Gnomad4 AFR exome AF: 0.0442

Gnomad4 AMR exome AF: 0.00424

Gnomad4 ASJ exome AF: 0.00348

Gnomad4 EAS exome AF: 0.0000324

Gnomad4 SAS exome AF: 0.000647

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00515

Gnomad4 OTH exome AF: 0.00729

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

Gnomad4 AFR AF: 0.0486

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0151

Gnomad4 NFE AF: 0.00518

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0138 Hom.: 6

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	- -

Fetal akinesia deformation sequence 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Congenital myasthenic syndrome 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.91

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: rs73459751; hg19: chr11-47459319;