rs770321568

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_000271.5(NPC1):c.1947+5G>C variant causes a splice donor 5th base, intron change. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000053 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NPC1
NM_000271.5 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.9998

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 5.79

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 18-23544955-C-G is Pathogenic according to our data. Variant chr18-23544955-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281945.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.1947+5G>C		splice_donor_5th_base_variant, intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.1947+5G>C	splice_donor_5th_base_variant, intron_variant	1	NM_000271.5	P1	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.1025+5G>C	splice_donor_5th_base_variant, intron_variant	2
NPC1	ENST00000540608.5 linkuse as main transcript	n.1861+5G>C	splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249836

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135240

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000531

AC:

AN:

1319098

Hom.:

Cov.:

AF XY:

0.00000604

AC XY:

AN XY:

661904

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000708

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 04, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NPC1 protein in which other variant(s) (p.Gly640Arg) have been determined to be pathogenic (PMID: 12955717, 27581084). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 12 (PMID: 28328115). Studies have shown that this variant alters NPC1 gene expression (PMID: 30202070). ClinVar contains an entry for this variant (Variation ID: 281945). This variant has been observed in individual(s) with Niemann-Pick Type C (PMID: 28328115). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 12 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 likely results in the loss of 25 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -

Niemann-Pick disease, type C

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 30, 2022

Variant summary: NPC1 c.1947+5G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 5' splicing donor site and three predict the variant weakens a 5' donor site. Experimental evidence supports these predictions indicating the variant affects mRNA splicing (Salman_2017). The variant allele was found at a frequency of 8e-06 in 249836 control chromosomes (gnomAD). c.1947+5G>C has been reported in the literature in individuals affected with Niemann-Pick Disease (e.g. Mazzacuva_2016, Salman_2017, Schultz_2018). These data indicate that the variant may be associated with disease. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 20, 2018

- -

NPC1-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2023

The NPC1 c.1947+5G>C variant is predicted to interfere with splicing. This variant has been reported in individuals with Niemann-Pick disease, type C (Salman et al. 2017. PubMed ID: 28328115; Table S1, Mazzacuva et al. 2016. PubMed ID: 27139891). In vitro functional studies demonstrate this variant affects splicing as well as has an effect on NPC1 function (Figure 1C and D, Salman et al 2017. PubMed ID: 28328115; Figure 1D, Schultz et al. 2018. PubMed ID: 30202070 ). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-21124919-C-G). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.17

Cadd

Benign

Dann

Benign

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: 5

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