Genetic Variant NM_000271.5:c.1554-1009G>A (chr18-23552736-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000271.5(NPC1):c.1554-1009G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Consequence

NPC1
NM_000271.5 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.123

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-23552736-C-T is Pathogenic according to our data. Variant chr18-23552736-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.1554-1009G>A		intron_variant	Intron 9 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.1554-1009G>A	intron_variant	Intron 9 of 24	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.833+2022G>A	intron_variant	Intron 4 of 17	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 link	n.1468-1009G>A	intron_variant	Intron 7 of 15	2
NPC1	ENST00000590301.1 link	n.229-1009G>A	intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:4

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 9 of the NPC1 gene. It does not directly change the encoded amino acid sequence of the NPC1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with biochemical and clinical features of Niemann-Pick type C disease (PMID: 20718790, 23593294, 25425405, 28480683, 29453517). This variant is also known as IVS9‚Äì1009G>A. ClinVar contains an entry for this variant (Variation ID: 553804). Studies have shown that this variant results in inclusion of a pseudoexon and introduces a premature termination codon (PMID: 19718781, 28167839). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Sep 13, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NPC1-related disorder

Pathogenic:1

Jul 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPC1 c.1554-1009G>A variant is predicted to interfere with splicing. This variant occurs within a deep intronic region and has been reported in the compound heterozygous state in patients with Niemann-Pick disease type C1 (Rodríguez-Pascau et al. 2009. PubMed ID: 19718781; Patients SEQ1 and 2 in Hastings et al. 2019. PubMed ID: 31639011; Zeiger et al. 2018. PubMed ID: 29453517). A functional study has shown that the c.1554-1009G>A variant promotes a pseudoexon insertion and interferes with normal splicing (Rodríguez-Pascau et al. 2009. PubMed ID: 19718781). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic or likely pathogenic by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/553804/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

DANN

Benign

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.38

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over