rs756815669

Positions:

• chr18-23539859-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000271.5(NPC1):​c.2747A>G​(p.Asn916Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N916N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 4.20

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000271.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3801886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.2747A>G	p.Asn916Ser	missense_variant	18/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.2747A>G	p.Asn916Ser	missense_variant	18/25	1	NM_000271.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251482 Hom.: 0 AF XY: 0.0000956 AC XY: 13 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

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: 0.000132

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461882 Hom.: 0 Cov.: 35 AF XY: 0.0000468 AC XY: 34 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Uncertain:7

Uncertain significance, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	May 06, 2015	Our laboratory reported dual molecular diagnoses inMTPAP (NM_018109.3, c.1468G>T) and NPC1 (NM_000271.3, c.839delT and c.2747A>G - phase unknown) in one individual with reported features of global developmental delay, developmental regression, central hypotonia, short stature, failure to thrive, familial neurodegenerative disease, cerebellar problems on brain MRI, absence like episodes, left hip dislocation, and constipation. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jul 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 916 of the NPC1 protein (p.Asn916Ser). This variant is present in population databases (rs756815669, gnomAD 0.02%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 27016452). ClinVar contains an entry for this variant (Variation ID: 374343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NPC1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	Reported in a patient who harbored a second NPC1 variant who also was homozygous for a variant in another gene that may have been responsible for the phenotype; phenotype information was not provided (Posey et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27959697, 27016452) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.044
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.31
Sift	Benign	0.53	T
Sift4G	Benign	0.81	T
Polyphen		0.029	B
Vest4		0.70
MutPred		0.48		Gain of catalytic residue at N916 (P = 0.0072);
MVP		0.83
MPC		0.21
ClinPred		0.047	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.65

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: rs756815669; hg19: chr18-21119823;