18-23544943-ACCCC-ACCCCCCCCCCC

Variant names:

• chr18-23544943-A-ACCCCCCC
• rs3837910
• NM_000271.5:c.1947+10_1947+16dupGGGGGGG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000271.5(NPC1):​c.1947+10_1947+16dupGGGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0026 (13 hom., cov: 0)
  • Exomes 𝑓: 0.0010 (24 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00265 (277/104626) while in subpopulation AMR AF = 0.00426 (38/8918). AF 95% confidence interval is 0.00319. There are 13 homozygotes in GnomAd4. There are 127 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 277 AN: 104578 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.00243

Gnomad AMI AF: 0.00313

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.000357

Gnomad EAS AF: 0.00416

Gnomad SAS AF: 0.00263

Gnomad FIN AF: 0.00202

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00258

Gnomad OTH AF: 0.00278

GnomAD4 exome AF: 0.00103 AC: 968 AN: 936564 Hom.: 24 Cov.: 19 AF XY: 0.00108 AC XY: 518 AN XY: 478542

African (AFR) AF: 0.000116 AC: 3 AN: 25936

American (AMR) AF: 0.00180 AC: 66 AN: 36632

Ashkenazi Jewish (ASJ) AF: 0.000473 AC: 10 AN: 21130

East Asian (EAS) AF: 0.00126 AC: 34 AN: 26966

South Asian (SAS) AF: 0.00260 AC: 186 AN: 71558

European-Finnish (FIN) AF: 0.00390 AC: 157 AN: 40296

Middle Eastern (MID) AF: 0.00163 AC: 7 AN: 4298

European-Non Finnish (NFE) AF: 0.000698 AC: 467 AN: 668826

Other (OTH) AF: 0.000929 AC: 38 AN: 40922

GnomAD4 genome AF: 0.00265 AC: 277 AN: 104626 Hom.: 13 Cov.: 0 AF XY: 0.00256 AC XY: 127 AN XY: 49560

African (AFR) AF: 0.00242 AC: 76 AN: 31404

American (AMR) AF: 0.00426 AC: 38 AN: 8918

Ashkenazi Jewish (ASJ) AF: 0.000357 AC: 1 AN: 2800

East Asian (EAS) AF: 0.00417 AC: 15 AN: 3600

South Asian (SAS) AF: 0.00264 AC: 8 AN: 3030

European-Finnish (FIN) AF: 0.00202 AC: 10 AN: 4950

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

European-Non Finnish (NFE) AF: 0.00258 AC: 123 AN: 47620

Other (OTH) AF: 0.00276 AC: 4 AN: 1448

ClinVar

Not reported in ClinVar

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;