rs11299077

Variant names:

• chr18-23543572-TAAAAAAAAAAA-T
• rs11299077
• NM_000271.5:c.2131-14_2131-4delTTTTTTTTTTT

Your query was ambiguous. Multiple possible variants found:

• chr18-23543572-TAAAAAAAAAAA-T
• chr18-23543572-TAAAAAAAAAAA-TAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAAAAAA
• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000271.5(NPC1):​c.2131-14_2131-4delTTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: NPC1 NM_000271.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.93
• Publications: 4 publications found

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]

NPC1 Gene-Disease associations (from GenCC):

• Niemann-Pick disease, type C1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
• Niemann-Pick disease type C, adult neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, juvenile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, late infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe early infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe perinatal form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.2131-14_2131-4delTTTTTTTTTTT		splice_region_variant, intron_variant	Intron 13 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.2131-14_2131-4delTTTTTTTTTTT		splice_region_variant, intron_variant	Intron 13 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1207-14_1207-4delTTTTTTTTTTT		splice_region_variant, intron_variant	Intron 6 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.2045-14_2045-4delTTTTTTTTTTT		splice_region_variant, intron_variant	Intron 11 of 15	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

Aug 29, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9

Splicing

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

Other links and lift over

dbSNP: rs11299077; hg19: chr18-21123536;