chr18-23544943-A-ACCCCCCCCC

Variant names:

• chr18-23544943-A-ACCCCCCCCC
• rs3837910
• NM_000271.5:c.1947+8_1947+16dupGGGGGGGGG

Variant summary

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

The NM_000271.5(NPC1):​c.1947+8_1947+16dupGGGGGGGGG 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 0.0024 (24 hom., cov: 0)
  • Exomes 𝑓: 0.00076 (10 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 nfe. GnomAd4 allele frequency = 0.00243 (254/104572) while in subpopulation NFE AF = 0.0033 (157/47592). AF 95% confidence interval is 0.00288. There are 24 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+8_1947+16dupGGGGGGGGG		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+17insGGGGGGGGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+16_1023+17insGGGGGGGGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+16_1861+17insGGGGGGGGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 254 AN: 104526 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.00134

Gnomad AMI AF: 0.00156

Gnomad AMR AF: 0.00246

Gnomad ASJ AF: 0.00178

Gnomad EAS AF: 0.00277

Gnomad SAS AF: 0.00198

Gnomad FIN AF: 0.000810

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00330

Gnomad OTH AF: 0.00486

GnomAD4 exome AF: 0.000764 AC: 716 AN: 936626 Hom.: 10 Cov.: 19 AF XY: 0.000846 AC XY: 405 AN XY: 478558

⚠️ 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: 25936

American (AMR) AF: 0.00106 AC: 39 AN: 36644

Ashkenazi Jewish (ASJ) AF: 0.000568 AC: 12 AN: 21140

East Asian (EAS) AF: 0.00104 AC: 28 AN: 26964

South Asian (SAS) AF: 0.00208 AC: 149 AN: 71556

European-Finnish (FIN) AF: 0.00228 AC: 92 AN: 40326

Middle Eastern (MID) AF: 0.000232 AC: 1 AN: 4306

European-Non Finnish (NFE) AF: 0.000546 AC: 365 AN: 668836

Other (OTH) AF: 0.000684 AC: 28 AN: 40918

⚠️ 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: 0.00243 AC: 254 AN: 104572 Hom.: 24 Cov.: 0 AF XY: 0.00212 AC XY: 105 AN XY: 49538

African (AFR) AF: 0.00134 AC: 42 AN: 31382

American (AMR) AF: 0.00246 AC: 22 AN: 8932

Ashkenazi Jewish (ASJ) AF: 0.00178 AC: 5 AN: 2802

East Asian (EAS) AF: 0.00278 AC: 10 AN: 3600

South Asian (SAS) AF: 0.00199 AC: 6 AN: 3022

European-Finnish (FIN) AF: 0.000810 AC: 4 AN: 4938

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

European-Non Finnish (NFE) AF: 0.00330 AC: 157 AN: 47592

Other (OTH) AF: 0.00483 AC: 7 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;