rs149111199

chr18-23533559-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000271.5(NPC1):c.3592-42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,587,172 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (5 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.134

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-23533559-C-G is Benign according to our data. Variant chr18-23533559-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 255699.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-23533559-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00224 (341/152350) while in subpopulation AMR AF= 0.00425 (65/15302). AF 95% confidence interval is 0.00342. There are 2 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.3592-42G>C		intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.3592-42G>C		intron_variant		1	NM_000271.5	P1

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 341 AN: 152232 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00251 AC: 626 AN: 249826 Hom.: 1 AF XY: 0.00259 AC XY: 351 AN XY: 135376

Gnomad AFR exome AF: 0.000438

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00805

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.000284

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00287 AC: 4118 AN: 1434822 Hom.: 5 Cov.: 25 AF XY: 0.00282 AC XY: 2018 AN XY: 715596

Gnomad4 AFR exome AF: 0.000304

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.000454

Gnomad4 NFE exome AF: 0.00321

Gnomad4 OTH exome AF: 0.00289

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152350 Hom.: 2 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74504

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00328

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00232

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.2
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs149111199; hg19: chr18-21113523;