chr18-23544943-A-ACCCC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

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
• 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 -12 ACMG points.

• BP6: Variant 18-23544943-A-ACCCC is Benign according to our data. Variant chr18-23544943-A-ACCCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 324 AR gene

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

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

African (AFR) AF: 0.00790 AC: 200 AN: 25330

American (AMR) AF: 0.0441 AC: 1532 AN: 34772

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 270 AN: 20244

East Asian (EAS) AF: 0.0322 AC: 812 AN: 25234

South Asian (SAS) AF: 0.0446 AC: 2978 AN: 66818

European-Finnish (FIN) AF: 0.0351 AC: 1340 AN: 38144

Middle Eastern (MID) AF: 0.00885 AC: 37 AN: 4182

European-Non Finnish (NFE) AF: 0.0177 AC: 11359 AN: 640460

Other (OTH) AF: 0.0208 AC: 812 AN: 39010

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

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

African (AFR) AF: 0.0286 AC: 888 AN: 31042

American (AMR) AF: 0.0638 AC: 552 AN: 8654

Ashkenazi Jewish (ASJ) AF: 0.00898 AC: 25 AN: 2784

East Asian (EAS) AF: 0.0763 AC: 265 AN: 3474

South Asian (SAS) AF: 0.0343 AC: 102 AN: 2976

European-Finnish (FIN) AF: 0.0274 AC: 132 AN: 4826

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.0217 AC: 1027 AN: 47408

Other (OTH) AF: 0.0299 AC: 43 AN: 1440

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0317 Hom.: 365

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Apr 05, 2013

Eurofins Ntd Llc (ga)

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

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

- -

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

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

- -

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

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: COSV105007429; COSMIC: COSV105007429;