NM_000271.5:c.57+3963G>A

Variant names:

• chr18-23582324-C-T
• rs1429934
• NM_000271.5:c.57+3963G>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.57+3963G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 152,064 control chromosomes in the GnomAD database, including 37,681 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 0.70 (37681 hom., cov: 32)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.456
• Publications: 14 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

Y_RNA (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.91 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.57+3963G>A		intron	N/A	NP_000262.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	ENST00000269228.10	TSL:1 MANE Select	c.57+3963G>A		intron	N/A	ENSP00000269228.4
	NPC1	ENST00000540608.5	TSL:2	n.201+3963G>A		intron	N/A
	Y_RNA	ENST00000362496.1	TSL:6	n.-203G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106569 AN: 151946 Hom.: 37655 Cov.: 32

Gnomad AFR AF: 0.728

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.671

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

GnomAD4 genome AF: 0.701 AC: 106659 AN: 152064 Hom.: 37681 Cov.: 32 AF XY: 0.706 AC XY: 52436 AN XY: 74322

African (AFR) AF: 0.728 AC: 30176 AN: 41458

American (AMR) AF: 0.756 AC: 11561 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2063 AN: 3470

East Asian (EAS) AF: 0.932 AC: 4830 AN: 5184

South Asian (SAS) AF: 0.758 AC: 3657 AN: 4824

European-Finnish (FIN) AF: 0.671 AC: 7085 AN: 10558

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.663 AC: 45031 AN: 67970

Other (OTH) AF: 0.671 AC: 1416 AN: 2110

Alfa AF: 0.674 Hom.: 95721

Bravo AF: 0.710

Asia WGS AF: 0.831 AC: 2890 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.1
DANN	Benign	0.67
PhyloP100		-0.46
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: rs1429934; hg19: chr18-21162288;