rs11663558

Variant names:

• chr18-23553973-G-A
• rs11663558
• NM_000271.5:c.1553+785C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000271.5(NPC1):​c.1553+785C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 151,986 control chromosomes in the GnomAD database, including 11,391 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (11391 hom., cov: 32)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.127
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• Niemann-Pick disease, type C1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
• Niemann-Pick disease type C, adult neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, juvenile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, late infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe early infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe perinatal form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1553+785C>T		intron_variant	Intron 9 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1553+785C>T		intron_variant	Intron 9 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.833+785C>T		intron_variant	Intron 4 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1467+785C>T		intron_variant	Intron 7 of 15	2
NPC1	ENST00000590301.1	n.228+785C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54971 AN: 151868 Hom.: 11381 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.328

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.362 AC: 55008 AN: 151986 Hom.: 11391 Cov.: 32 AF XY: 0.365 AC XY: 27099 AN XY: 74280

African (AFR) AF: 0.155 AC: 6427 AN: 41498

American (AMR) AF: 0.460 AC: 7020 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 940 AN: 3466

East Asian (EAS) AF: 0.411 AC: 2116 AN: 5150

South Asian (SAS) AF: 0.391 AC: 1880 AN: 4808

European-Finnish (FIN) AF: 0.507 AC: 5344 AN: 10546

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.443 AC: 30121 AN: 67930

Other (OTH) AF: 0.333 AC: 702 AN: 2110

Alfa AF: 0.407 Hom.: 44504

Bravo AF: 0.351

Asia WGS AF: 0.403 AC: 1400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.75
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11663558; hg19: chr18-21133937;