18-23531886-CCTTTACA-C

Position:

• chr18-23531886-CCTTTACA-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000271.5(NPC1):​c.*309_*315delTGTAAAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,443,394 control chromosomes in the GnomAD database, including 74 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0064 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (65 hom.)
• Consequence: NPC1 NM_000271.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.86

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 18-23531886-CCTTTACA-C is Benign according to our data. Variant chr18-23531886-CCTTTACA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 326243.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00641 (970/151368) while in subpopulation NFE AF= 0.0091 (618/67926). AF 95% confidence interval is 0.0085. There are 9 homozygotes in gnomad4. There are 496 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.*309_*315delTGTAAAG		3_prime_UTR_variant	25/25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228	c.*309_*315delTGTAAAG		3_prime_UTR_variant	25/25	1	NM_000271.5	ENSP00000269228.4

Frequencies

GnomAD3 genomes AF: 0.00641 AC: 970 AN: 151252 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00238

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00385

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00911

Gnomad OTH AF: 0.00434

GnomAD4 exome AF: 0.00804 AC: 10391 AN: 1292026 Hom.: 65 AF XY: 0.00789 AC XY: 4960 AN XY: 628432

Gnomad4 AFR exome AF: 0.000846

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.000315

Gnomad4 EAS exome AF: 0.0000285

Gnomad4 SAS exome AF: 0.00452

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.00882

Gnomad4 OTH exome AF: 0.00549

GnomAD4 genome AF: 0.00641 AC: 970 AN: 151368 Hom.: 9 Cov.: 32 AF XY: 0.00671 AC XY: 496 AN XY: 73876

Gnomad4 AFR AF: 0.00114

Gnomad4 AMR AF: 0.00237

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00407

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.00910

Gnomad4 OTH AF: 0.00429

Alfa AF: 0.00923 Hom.: 0

Bravo AF: 0.00455

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	NPC1: BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Niemann-Pick disease, type C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145236115; hg19: chr18-21111850;