chr18-23544943-A-ACCCCC

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

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
• 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: Likely_benign. The variant received -6 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 VariationId is 1157450.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 488 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.1947+12_1947+16dupGGGGG		intron	N/A	NP_000262.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	ENST00000269228.10	TSL:1 MANE Select	c.1947+16_1947+17insGGGGG		intron	N/A	ENSP00000269228.4
	NPC1	ENST00000591051.1	TSL:2	c.1023+16_1023+17insGGGGG		intron	N/A	ENSP00000467636.1
	NPC1	ENST00000540608.5	TSL:2	n.1861+16_1861+17insGGGGG		intron	N/A

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

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

African (AFR) AF: 0.00136 AC: 35 AN: 25810

American (AMR) AF: 0.00658 AC: 239 AN: 36348

Ashkenazi Jewish (ASJ) AF: 0.00399 AC: 83 AN: 20790

East Asian (EAS) AF: 0.00635 AC: 168 AN: 26452

South Asian (SAS) AF: 0.00755 AC: 534 AN: 70762

European-Finnish (FIN) AF: 0.00927 AC: 366 AN: 39464

Middle Eastern (MID) AF: 0.00328 AC: 14 AN: 4266

European-Non Finnish (NFE) AF: 0.00397 AC: 2619 AN: 659328

Other (OTH) AF: 0.00523 AC: 210 AN: 40168

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

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

African (AFR) AF: 0.0111 AC: 348 AN: 31244

American (AMR) AF: 0.0201 AC: 177 AN: 8802

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 80 AN: 2766

East Asian (EAS) AF: 0.0330 AC: 116 AN: 3512

South Asian (SAS) AF: 0.0602 AC: 176 AN: 2924

European-Finnish (FIN) AF: 0.0422 AC: 198 AN: 4688

Middle Eastern (MID) AF: 0.00476 AC: 1 AN: 210

European-Non Finnish (NFE) AF: 0.0525 AC: 2434 AN: 46378

Other (OTH) AF: 0.0254 AC: 36 AN: 1420

⚠️ 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: 0.0180 Hom.: 365

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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 v4.9

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;