18-23543572-TAAAAAAAAAAA-TAAAAAAAAA

Position:

• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAA

Variant summary

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

The NM_000271.5(NPC1):​c.2131-5_2131-4del variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0610

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-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/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.2131-5_2131-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.2131-5_2131-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000591051.1	c.1209-5_1209-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000467636
NPC1	ENST00000540608.5	n.2045-5_2045-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2282 AN: 143442 Hom.: 39 Cov.: 0

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.: 8 AF XY: 0.244 AC XY: 23270 AN XY: 95426

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.: 10 AF XY: 0.157 AC XY: 81157 AN XY: 518502

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.: 41 Cov.: 0 AF XY: 0.0162 AC XY: 1125 AN XY: 69456

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

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Apr 21, 2020	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jun 06, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 06, 2017	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2019	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

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;