18-23544943-ACCCC-ACCCCCCCCCCCC

Variant names:

• chr18-23544943-A-ACCCCCCCC
• rs3837910
• NM_000271.5:c.1947+9_1947+16dupGGGGGGGG

Variant summary

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

The NM_000271.5(NPC1):​c.1947+9_1947+16dupGGGGGGGG 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 0.021 (180 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (24 hom.)
  • Failed GnomAD Quality Control
• 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 sas. GnomAdExome4 allele frequency = 0.00118 (1105/936232) while in subpopulation SAS AF = 0.00327 (234/71478). AF 95% confidence interval is 0.00293. There are 24 homozygotes in GnomAdExome4. There are 616 alleles in the male GnomAdExome4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+9_1947+16dupGGGGGGGG		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+17insGGGGGGGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+16_1023+17insGGGGGGGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+16_1861+17insGGGGGGGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 2215 AN: 104096 Hom.: 179 Cov.: 0

Gnomad AFR AF: 0.00861

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.0175

Gnomad SAS AF: 0.0142

Gnomad FIN AF: 0.00833

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.0339

Gnomad OTH AF: 0.0174

GnomAD4 exome AF: 0.00118 AC: 1105 AN: 936232 Hom.: 24 Cov.: 19 AF XY: 0.00129 AC XY: 616 AN XY: 478366

African (AFR) AF: 0.000116 AC: 3 AN: 25926

American (AMR) AF: 0.00128 AC: 47 AN: 36628

Ashkenazi Jewish (ASJ) AF: 0.000521 AC: 11 AN: 21124

East Asian (EAS) AF: 0.00126 AC: 34 AN: 26960

South Asian (SAS) AF: 0.00327 AC: 234 AN: 71478

European-Finnish (FIN) AF: 0.00402 AC: 162 AN: 40270

Middle Eastern (MID) AF: 0.000465 AC: 2 AN: 4302

European-Non Finnish (NFE) AF: 0.000845 AC: 565 AN: 668626

Other (OTH) AF: 0.00115 AC: 47 AN: 40918

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0213 AC: 2217 AN: 104142 Hom.: 180 Cov.: 0 AF XY: 0.0174 AC XY: 860 AN XY: 49368

African (AFR) AF: 0.00865 AC: 271 AN: 31342

American (AMR) AF: 0.0111 AC: 99 AN: 8918

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 52 AN: 2772

East Asian (EAS) AF: 0.0175 AC: 63 AN: 3590

South Asian (SAS) AF: 0.0143 AC: 43 AN: 3016

European-Finnish (FIN) AF: 0.00833 AC: 41 AN: 4922

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

European-Non Finnish (NFE) AF: 0.0339 AC: 1601 AN: 47282

Other (OTH) AF: 0.0173 AC: 25 AN: 1446

Alfa AF: 0.00951 Hom.: 365

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;