18-23554275-C-T

Variant names:

• chr18-23554275-C-T
• rs1631685
• NM_000271.5:c.1553+483G>A

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+483G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 151,944 control chromosomes in the GnomAD database, including 26,862 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 0.58 (26862 hom., cov: 31)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 12 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, G2P
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.1553+483G>A		intron	N/A	NP_000262.2	O15118-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	ENST00000269228.10	TSL:1 MANE Select	c.1553+483G>A		intron	N/A	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.1604+483G>A		intron	N/A	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.1553+483G>A		intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88123 AN: 151826 Hom.: 26822 Cov.: 31

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.914

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.518

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

GnomAD4 genome AF: 0.581 AC: 88226 AN: 151944 Hom.: 26862 Cov.: 31 AF XY: 0.584 AC XY: 43363 AN XY: 74244

African (AFR) AF: 0.719 AC: 29814 AN: 41444

American (AMR) AF: 0.619 AC: 9459 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1088 AN: 3464

East Asian (EAS) AF: 0.914 AC: 4709 AN: 5154

South Asian (SAS) AF: 0.581 AC: 2801 AN: 4820

European-Finnish (FIN) AF: 0.534 AC: 5632 AN: 10548

Middle Eastern (MID) AF: 0.360 AC: 105 AN: 292

European-Non Finnish (NFE) AF: 0.487 AC: 33080 AN: 67922

Other (OTH) AF: 0.524 AC: 1106 AN: 2110

Alfa AF: 0.516 Hom.: 11016

Bravo AF: 0.597

Asia WGS AF: 0.731 AC: 2539 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.071
DANN	Benign	0.27
PhyloP100		-1.4
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: rs1631685; hg19: chr18-21134239;