chr18-23544943-A-ACCCCCCCCCC

Variant names:

• chr18-23544943-A-ACCCCCCCCCC
• rs3837910
• NM_000271.5:c.1947+16_1947+17insGGGGGGGGGG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000271.5(NPC1):​c.1947+16_1947+17insGGGGGGGGGG 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 (252 hom., cov: 0)
  • Exomes 𝑓: 0.00065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.952
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 2194 AN: 103974 Hom.: 252 Cov.: 0

Gnomad AFR AF: 0.00803

Gnomad AMI AF: 0.0334

Gnomad AMR AF: 0.00809

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00934

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.000651 AC: 610 AN: 936774 Hom.: 0 Cov.: 19 AF XY: 0.000635 AC XY: 304 AN XY: 478652

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

African (AFR) AF: 0.0000771 AC: 2 AN: 25934

American (AMR) AF: 0.000791 AC: 29 AN: 36656

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 8 AN: 21144

East Asian (EAS) AF: 0.00111 AC: 30 AN: 26978

South Asian (SAS) AF: 0.00166 AC: 119 AN: 71574

European-Finnish (FIN) AF: 0.000967 AC: 39 AN: 40322

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

European-Non Finnish (NFE) AF: 0.000531 AC: 355 AN: 668926

Other (OTH) AF: 0.000660 AC: 27 AN: 40936

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0211 AC: 2194 AN: 104022 Hom.: 252 Cov.: 0 AF XY: 0.0174 AC XY: 860 AN XY: 49344

African (AFR) AF: 0.00801 AC: 251 AN: 31346

American (AMR) AF: 0.00809 AC: 72 AN: 8902

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 68 AN: 2776

East Asian (EAS) AF: 0.00946 AC: 34 AN: 3594

South Asian (SAS) AF: 0.0189 AC: 57 AN: 3016

European-Finnish (FIN) AF: 0.00934 AC: 46 AN: 4924

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

European-Non Finnish (NFE) AF: 0.0343 AC: 1620 AN: 47180

Other (OTH) AF: 0.0167 AC: 24 AN: 1440

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;