rs11299077

chr18-23543572-TAAAAAAAAAAA-Tchr18-23543572-TAAAAAAAAAAA-TAAAAAAchr18-23543572-TAAAAAAAAAAA-TAAAAAAAchr18-23543572-TAAAAAAAAAAA-TAAAAAAAAchr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAchr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAchr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAAchr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAAAchr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAAAA

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000271.5(NPC1):c.2131-14_2131-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: NPC1 NM_000271.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.93

Genes affected

NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.2131-14_2131-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.2131-14_2131-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.1209-14_1209-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2
NPC1	ENST00000540608.5	n.2045-14_2045-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 0

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2017

The c.2131-14_2131-4del11 variant in the NPC1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is predicted to destroy the splice acceptor site in intron 13, and is expected to cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of c.2131-14_2131-4del11 in this individual is unknown. The c.2131-14_2131-4del11 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.2131-14_2131-4del11 as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11299077; hg19: chr18-21123536;