18-23544943-A-ACCC

Variant names:

• chr18-23544943-A-ACCC
• rs3837910
• NM_000271.5:c.1947+14_1947+16dupGGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000271.5(NPC1):​c.1947+14_1947+16dupGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (1198 hom., cov: 0)
  • Exomes 𝑓: 0.052 (1185 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.952
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 18-23544943-A-ACCC is Benign according to our data. Variant chr18-23544943-A-ACCC is described in ClinVar as Benign. ClinVar VariationId is 418387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+14_1947+16dupGGG		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+17insGGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+16_1023+17insGGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+16_1861+17insGGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 9510 AN: 103112 Hom.: 1198 Cov.: 0

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.0312

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.0612

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.0342

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0968

GnomAD4 exome AF: 0.0519 AC: 45165 AN: 869952 Hom.: 1185 Cov.: 19 AF XY: 0.0531 AC XY: 23563 AN XY: 443876

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0853 AC: 2015 AN: 23612

American (AMR) AF: 0.138 AC: 4510 AN: 32734

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 425 AN: 19958

East Asian (EAS) AF: 0.113 AC: 2716 AN: 24082

South Asian (SAS) AF: 0.0862 AC: 5562 AN: 64542

European-Finnish (FIN) AF: 0.0653 AC: 2453 AN: 37592

Middle Eastern (MID) AF: 0.0274 AC: 112 AN: 4086

European-Non Finnish (NFE) AF: 0.0407 AC: 25472 AN: 625502

Other (OTH) AF: 0.0502 AC: 1900 AN: 37844

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0924 AC: 9529 AN: 103150 Hom.: 1198 Cov.: 0 AF XY: 0.0937 AC XY: 4580 AN XY: 48882

African (AFR) AF: 0.196 AC: 5957 AN: 30406

American (AMR) AF: 0.0938 AC: 826 AN: 8810

Ashkenazi Jewish (ASJ) AF: 0.0312 AC: 87 AN: 2788

East Asian (EAS) AF: 0.177 AC: 622 AN: 3516

South Asian (SAS) AF: 0.0615 AC: 185 AN: 3008

European-Finnish (FIN) AF: 0.0170 AC: 83 AN: 4892

Middle Eastern (MID) AF: 0.0374 AC: 8 AN: 214

European-Non Finnish (NFE) AF: 0.0342 AC: 1623 AN: 47454

Other (OTH) AF: 0.0970 AC: 138 AN: 1422

Alfa AF: 0.0469 Hom.: 365

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 13, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

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:3

Oct 19, 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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

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

Mar 05, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3837910; hg19: chr18-21124907; COSMIC: COSV52577913; COSMIC: COSV52577913;