rs4800488

Positions:

• chr18-23537607-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000271.5(NPC1):​c.3042-731G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 151,970 control chromosomes in the GnomAD database, including 17,097 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 0.47 (17097 hom., cov: 31)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.3042-731G>T		intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.3042-731G>T		intron_variant		1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.2120-731G>T		intron_variant		2
NPC1	ENST00000591075.1	n.675-731G>T		intron_variant, non_coding_transcript_variant		4
NPC1	ENST00000591955.1	n.385-731G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71278 AN: 151850 Hom.: 17081 Cov.: 31

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.470 AC: 71352 AN: 151970 Hom.: 17097 Cov.: 31 AF XY: 0.474 AC XY: 35178 AN XY: 74242

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.574

Gnomad4 ASJ AF: 0.308

Gnomad4 EAS AF: 0.625

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.446

Alfa AF: 0.472 Hom.: 8704

Bravo AF: 0.474

Asia WGS AF: 0.553 AC: 1921 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.56

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: rs4800488; hg19: chr18-21117571;