18-23535033-C-T

Position:

• chr18-23535033-C-T

Variant summary

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

The NM_000271.5(NPC1):​c.3477+436G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 151,880 control chromosomes in the GnomAD database, including 11,455 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 (11455 hom., cov: 31)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.400

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=-1.03).
• 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/exons	MANE	UniProt
NPC1	NM_000271.5	c.3477+436G>A		intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.3477+436G>A		intron_variant		1	NM_000271.5	P1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54215 AN: 151762 Hom.: 11445 Cov.: 31

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.324

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

GnomAD4 genome AF: 0.357 AC: 54248 AN: 151880 Hom.: 11455 Cov.: 31 AF XY: 0.359 AC XY: 26674 AN XY: 74214

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.460

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.412

Gnomad4 SAS AF: 0.391

Gnomad4 FIN AF: 0.513

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.329

Alfa AF: 0.416 Hom.: 12801

Bravo AF: 0.344

Asia WGS AF: 0.409 AC: 1421 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.071
DANN	Benign	0.56

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: rs2236707; hg19: chr18-21114997;