rs80358251

chr18-23560403-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_000271.5(NPC1):c.709C>T(p.Pro237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,168 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P237L) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 32)
  • Exomes 𝑓: 0.014 (178 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14 O:1
• Conservation: PhyloP100: 8.19

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 -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-23560402-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.013225466).
• BP6: Variant 18-23560403-G-A is Benign according to our data. Variant chr18-23560403-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21142.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=2, not_provided=1}. Variant chr18-23560403-G-A is described in Lovd as [Benign]. Variant chr18-23560403-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.01 (1528/152344) while in subpopulation NFE AF= 0.0162 (1100/68034). AF 95% confidence interval is 0.0154. There are 17 homozygotes in gnomad4. There are 720 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.709C>T	p.Pro237Ser	missense_variant	6/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.709C>T	p.Pro237Ser	missense_variant	6/25	1	NM_000271.5	P1
NPC1	ENST00000540608.5	n.623C>T		non_coding_transcript_exon_variant	4/16	2

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1530 AN: 152226 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00988 AC: 2478 AN: 250694 Hom.: 26 AF XY: 0.00961 AC XY: 1302 AN XY: 135546

Gnomad AFR exome AF: 0.00296

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00289

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.0138 AC: 20169 AN: 1461824 Hom.: 178 Cov.: 32 AF XY: 0.0133 AC XY: 9695 AN XY: 727222

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00423

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.0198

Gnomad4 NFE exome AF: 0.0161

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0100 AC: 1528 AN: 152344 Hom.: 17 Cov.: 32 AF XY: 0.00966 AC XY: 720 AN XY: 74510

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0186

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.0140 Hom.: 20

Bravo AF: 0.00840

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0159 AC: 137

ExAC AF: 0.0104 AC: 1263

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.0144

EpiControl AF: 0.0133

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type C1 Uncertain:1 Benign:5 Other:1

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Niemann-Pick disease, type C1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:12554680). BS1 => Allele frequency is greater than expected for disorder (PMID:11182931). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Aug 22, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32222928, 29631617, 28328115, 25842391, 10480349, 20981092, 12955717, 12554680, 22995991, 25497598, 20489167) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2018	- -

Nasopharyngeal carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	21
Dann	Benign	0.85
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.012
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.40
Sift	Benign	0.41	T
Sift4G	Benign	0.52	T
Polyphen		0.0030	B
Vest4		0.42
MPC		0.27
ClinPred		0.076	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80358251; hg19: chr18-21140367; COSMIC: COSV99036290; COSMIC: COSV99036290;