chr11-47447927-A-G

Position:

• chr11-47447927-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_005055.5(RAPSN):​c.416T>C​(p.Phe139Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.69

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a repeat TPR 3 (size 33) in uniprot entity RAPSN_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 11-47447927-A-G is Pathogenic according to our data. Variant chr11-47447927-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 8058.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-47447927-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.416T>C	p.Phe139Ser	missense_variant	2/8	ENST00000298854.7	NP_005046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7	c.416T>C	p.Phe139Ser	missense_variant	2/8	1	NM_005055.5	ENSP00000298854	P1
RAPSN	ENST00000352508.7	c.416T>C	p.Phe139Ser	missense_variant	2/6	1		ENSP00000298853
RAPSN	ENST00000529341.1	c.416T>C	p.Phe139Ser	missense_variant	2/5	1		ENSP00000431732
RAPSN	ENST00000524487.5	c.416T>C	p.Phe139Ser	missense_variant	2/7	5		ENSP00000435551

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Fetal akinesia deformation sequence 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.97	L;L;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D;D;D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;P
Vest4		0.96
MutPred		0.89		Gain of disorder (P = 0.0078);Gain of disorder (P = 0.0078);Gain of disorder (P = 0.0078);Gain of disorder (P = 0.0078);
MVP		0.94
MPC		0.89
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121909256; hg19: chr11-47469479;