18-23543572-TAAAAAAAAAAA-TAAAAAAAAAA

Position:

• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000271.5(NPC1):​c.2131-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (30714 hom., cov: 0)
  • Exomes 𝑓: 0.44 (4735 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPC1 NM_000271.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.485

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 18-23543572-TA-T is Benign according to our data. Variant chr18-23543572-TA-T is described in ClinVar as [Benign]. Clinvar id is 403254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23543572-TA-T is described in Lovd as [Benign]. Variant chr18-23543572-TA-T is described in Lovd as [Benign]. Variant chr18-23543572-TA-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.646 AC: 92677 AN: 143532 Hom.: 30711 Cov.: 0

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.632

GnomAD3 exomes AF: 0.461 AC: 79877 AN: 173230 Hom.: 302 AF XY: 0.461 AC XY: 43967 AN XY: 95426

Gnomad AFR exome AF: 0.466

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.475

Gnomad SAS exome AF: 0.466

Gnomad FIN exome AF: 0.456

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.459

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.440 AC: 460275 AN: 1046340 Hom.: 4735 Cov.: 0 AF XY: 0.442 AC XY: 236417 AN XY: 534492

Gnomad4 AFR exome AF: 0.477

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.452

Gnomad4 EAS exome AF: 0.490

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.450

Gnomad4 NFE exome AF: 0.431

Gnomad4 OTH exome AF: 0.447

GnomAD4 genome AF: 0.646 AC: 92715 AN: 143600 Hom.: 30714 Cov.: 0 AF XY: 0.651 AC XY: 45271 AN XY: 69538

Gnomad4 AFR AF: 0.823

Gnomad4 AMR AF: 0.686

Gnomad4 ASJ AF: 0.529

Gnomad4 EAS AF: 0.892

Gnomad4 SAS AF: 0.739

Gnomad4 FIN AF: 0.535

Gnomad4 NFE AF: 0.527

Gnomad4 OTH AF: 0.633

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:7

Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Apr 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jun 06, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	East Asian population allele frequency is 46.48% (rs752453963, 7475/14430 alleles, 629 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.3.0, this variant is classified as BENIGN. Following criteria are met: BA1 -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 13, 2016	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs11299077; hg19: chr18-21123536;