NM_000271.5:c.1947+11_1947+16dupGGGGGG

Variant names:

• chr18-23544943-A-ACCCCCC
• rs3837910
• NM_000271.5:c.1947+11_1947+16dupGGGGGG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000271.5(NPC1):​c.1947+11_1947+16dupGGGGGG 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 0.0028 (17 hom., cov: 0)
  • Exomes 𝑓: 0.00090 (27 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 18-23544943-A-ACCCCCC is Benign according to our data. Variant chr18-23544943-A-ACCCCCC is described in ClinVar as Likely_benign. ClinVar VariationId is 1574507.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00285 (298/104564) while in subpopulation EAS AF = 0.00836 (30/3590). AF 95% confidence interval is 0.00601. There are 17 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+11_1947+16dupGGGGGG		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+17insGGGGGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+16_1023+17insGGGGGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+16_1861+17insGGGGGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 299 AN: 104516 Hom.: 17 Cov.: 0

Gnomad AFR AF: 0.00230

Gnomad AMI AF: 0.00469

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.00286

Gnomad EAS AF: 0.00861

Gnomad SAS AF: 0.00231

Gnomad FIN AF: 0.00121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00313

Gnomad OTH AF: 0.00208

GnomAD4 exome AF: 0.000897 AC: 840 AN: 936310 Hom.: 27 Cov.: 19 AF XY: 0.000945 AC XY: 452 AN XY: 478426

African (AFR) AF: 0.000270 AC: 7 AN: 25922

American (AMR) AF: 0.00106 AC: 39 AN: 36630

Ashkenazi Jewish (ASJ) AF: 0.000331 AC: 7 AN: 21132

East Asian (EAS) AF: 0.00149 AC: 40 AN: 26910

South Asian (SAS) AF: 0.00211 AC: 151 AN: 71618

European-Finnish (FIN) AF: 0.00415 AC: 167 AN: 40278

Middle Eastern (MID) AF: 0.000232 AC: 1 AN: 4304

European-Non Finnish (NFE) AF: 0.000591 AC: 395 AN: 668600

Other (OTH) AF: 0.000807 AC: 33 AN: 40916

GnomAD4 genome AF: 0.00285 AC: 298 AN: 104564 Hom.: 17 Cov.: 0 AF XY: 0.00283 AC XY: 140 AN XY: 49528

African (AFR) AF: 0.00229 AC: 72 AN: 31386

American (AMR) AF: 0.00224 AC: 20 AN: 8930

Ashkenazi Jewish (ASJ) AF: 0.00286 AC: 8 AN: 2800

East Asian (EAS) AF: 0.00836 AC: 30 AN: 3590

South Asian (SAS) AF: 0.00232 AC: 7 AN: 3022

European-Finnish (FIN) AF: 0.00121 AC: 6 AN: 4942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00313 AC: 149 AN: 47590

Other (OTH) AF: 0.00207 AC: 3 AN: 1448

Alfa AF: 0.00 Hom.: 365

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.95

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;