18-23544943-ACCCC-ACCCCCCCC

Variant names:

• chr18-23544943-A-ACCCC
• rs3837910
• NM_000271.5:c.1947+13_1947+16dupGGGG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000271.5(NPC1):​c.1947+13_1947+16dupGGGG 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 0.030 (324 hom., cov: 0)
  • Exomes 𝑓: 0.022 (244 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• 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 -16 ACMG points.

• BP6: Variant 18-23544943-A-ACCCC is Benign according to our data. Variant chr18-23544943-A-ACCCC is described in ClinVar as [Likely_benign]. Clinvar id is 92703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+13_1947+16dupGGGG		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+17insGGGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+16_1023+17insGGGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+16_1861+17insGGGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 3065 AN: 103412 Hom.: 324 Cov.: 0

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.0455

Gnomad AMR AF: 0.0638

Gnomad ASJ AF: 0.00898

Gnomad EAS AF: 0.0761

Gnomad SAS AF: 0.0344

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0300

GnomAD4 exome AF: 0.0216 AC: 19340 AN: 894194 Hom.: 244 Cov.: 19 AF XY: 0.0226 AC XY: 10333 AN XY: 456352

Gnomad4 AFR exome AF: 0.00790

Gnomad4 AMR exome AF: 0.0441

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.0322

Gnomad4 SAS exome AF: 0.0446

Gnomad4 FIN exome AF: 0.0351

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0208

GnomAD4 genome AF: 0.0296 AC: 3064 AN: 103458 Hom.: 324 Cov.: 0 AF XY: 0.0294 AC XY: 1437 AN XY: 48950

Gnomad4 AFR AF: 0.0286

Gnomad4 AMR AF: 0.0638

Gnomad4 ASJ AF: 0.00898

Gnomad4 EAS AF: 0.0763

Gnomad4 SAS AF: 0.0343

Gnomad4 FIN AF: 0.0274

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.0299

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 05, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Niemann-Pick disease, type C1 Benign:4

May 22, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 06, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NPC1-related disorder Benign:1

Sep 15, 2023

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). -

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;