18-23543572-TAAAAAAAAAAA-TAAAAAAAAA

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000271.5(NPC1):c.2131-5_2131-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,160,146 control chromosomes in the GnomAD database, including 51 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 41 hom., cov: 0)

Exomes 𝑓: 0.15 ( 10 hom. )

Consequence

NPC1
NM_000271.5 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0610

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 Benign. Variant got -16 ACMG points.

BP6

Variant 18-23543572-TAA-T is Benign according to our data. Variant chr18-23543572-TAA-T is described in ClinVar as [Benign]. Clinvar id is 522212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23543572-TAA-T is described in Lovd as [Benign]. Variant chr18-23543572-TAA-T is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.2131-5_2131-4delTT	splice_region_variant, intron_variant	Intron 13 of 24	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.1207-5_1207-4delTT	splice_region_variant, intron_variant	Intron 6 of 17	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 link	n.2045-5_2045-4delTT	splice_region_variant, intron_variant	Intron 11 of 15	2

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2282

AN:

143442

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0422

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00831

Gnomad ASJ

AF:

0.00179

Gnomad EAS

AF:

0.0284

Gnomad SAS

AF:

0.0127

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.00980

Gnomad NFE

AF:

0.00271

Gnomad OTH

AF:

0.0145

GnomAD3 exomes

AF:

0.246

AC:

42576

AN:

173230

Hom.:

AF XY:

0.244

AC XY:

23270

AN XY:

95426

show subpopulations

Gnomad AFR exome

AF:

0.382

Gnomad AMR exome

AF:

0.292

Gnomad ASJ exome

AF:

0.156

Gnomad EAS exome

AF:

0.398

Gnomad SAS exome

AF:

0.285

Gnomad FIN exome

AF:

0.197

Gnomad NFE exome

AF:

0.195

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

AF:

0.153

AC:

156025

AN:

1016642

Hom.:

AF XY:

0.157

AC XY:

81157

AN XY:

518502

show subpopulations

Gnomad4 AFR exome

AF:

0.309

Gnomad4 AMR exome

AF:

0.270

Gnomad4 ASJ exome

AF:

0.134

Gnomad4 EAS exome

AF:

0.375

Gnomad4 SAS exome

AF:

0.243

Gnomad4 FIN exome

AF:

0.145

Gnomad4 NFE exome

AF:

0.127

Gnomad4 OTH exome

AF:

0.162

GnomAD4 genome

AF:

0.0161

AC:

2304

AN:

143504

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

1125

AN XY:

69456

show subpopulations

Gnomad4 AFR

AF:

0.0426

Gnomad4 AMR

AF:

0.00830

Gnomad4 ASJ

AF:

0.00179

Gnomad4 EAS

AF:

0.0285

Gnomad4 SAS

AF:

0.0132

Gnomad4 FIN

AF:

0.0116

Gnomad4 NFE

AF:

0.00271

Gnomad4 OTH

AF:

0.0154

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Benign:4

Sep 27, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 06, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 21, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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