chr18-23544943-A-ACCCCC

Variant names:

• chr18-23544943-A-ACCCCC
• rs3837910
• NM_000271.5:c.1947+12_1947+16dupGGGGG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000271.5(NPC1):​c.1947+12_1947+16dupGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.035 (488 hom., cov: 0)
  • Exomes 𝑓: 0.0046 (58 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -0.952

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 -10 ACMG points.

• BP6: Variant 18-23544943-A-ACCCCC is Benign according to our data. Variant chr18-23544943-A-ACCCCC is described in ClinVar as [Likely_benign]. Clinvar id is 1157450.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+12_1947+16dupGGGGG		intron_variant	Intron 12 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+16_1947+17insGGGGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+16_1023+17insGGGGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+16_1861+17insGGGGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.0352 AC: 3605 AN: 102516 Hom.: 488 Cov.: 0

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0645

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.0332

Gnomad SAS AF: 0.0599

Gnomad FIN AF: 0.0422

Gnomad MID AF: 0.00435

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.0255

GnomAD4 exome AF: 0.00462 AC: 4268 AN: 923388 Hom.: 58 Cov.: 19 AF XY: 0.00476 AC XY: 2245 AN XY: 471788

Gnomad4 AFR exome AF: 0.00136

Gnomad4 AMR exome AF: 0.00658

Gnomad4 ASJ exome AF: 0.00399

Gnomad4 EAS exome AF: 0.00635

Gnomad4 SAS exome AF: 0.00755

Gnomad4 FIN exome AF: 0.00927

Gnomad4 NFE exome AF: 0.00397

Gnomad4 OTH exome AF: 0.00523

GnomAD4 genome AF: 0.0352 AC: 3606 AN: 102564 Hom.: 488 Cov.: 0 AF XY: 0.0353 AC XY: 1714 AN XY: 48510

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0289

Gnomad4 EAS AF: 0.0330

Gnomad4 SAS AF: 0.0602

Gnomad4 FIN AF: 0.0422

Gnomad4 NFE AF: 0.0525

Gnomad4 OTH AF: 0.0254

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NPC1-related disorder Benign:1

Mar 24, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Niemann-Pick disease, type C1 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs3837910; hg19: chr18-21124907;