18-23543572-TAAAAAAAAAAA-TAAAAAAA

Variant names:

• chr18-23543572-TAAAA-T
• rs11299077
• NM_000271.5:c.2131-7_2131-4delTTTT

Variant summary

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

The NM_000271.5(NPC1):​c.2131-7_2131-4delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,204,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: NPC1 NM_000271.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.136
• Publications: 4 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, G2P
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.2131-7_2131-4delTTTT		splice_region intron	N/A	NP_000262.2	O15118-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	ENST00000269228.10	TSL:1 MANE Select	c.2131-7_2131-4delTTTT		splice_region intron	N/A	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.2182-7_2182-4delTTTT		splice_region intron	N/A	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.2131-7_2131-4delTTTT		splice_region intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.00000696 AC: 1 AN: 143576 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000219 AC: 38 AN: 173230 AF XY: 0.000199

Gnomad AFR exome AF: 0.0000912

Gnomad AMR exome AF: 0.000369

Gnomad ASJ exome AF: 0.000131

Gnomad EAS exome AF: 0.000309

Gnomad FIN exome AF: 0.000190

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.000375 AC: 398 AN: 1060562 Hom.: 0 AF XY: 0.000321 AC XY: 174 AN XY: 542036

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

African (AFR) AF: 0.000968 AC: 23 AN: 23756

American (AMR) AF: 0.000344 AC: 13 AN: 37774

Ashkenazi Jewish (ASJ) AF: 0.000178 AC: 4 AN: 22514

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35714

South Asian (SAS) AF: 0.000307 AC: 22 AN: 71690

European-Finnish (FIN) AF: 0.0000499 AC: 2 AN: 40070

Middle Eastern (MID) AF: 0.000426 AC: 2 AN: 4692

European-Non Finnish (NFE) AF: 0.000406 AC: 316 AN: 777916

Other (OTH) AF: 0.000258 AC: 12 AN: 46436

⚠️ 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: 0.00000696 AC: 1 AN: 143640 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 69540

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

African (AFR) AF: 0.00 AC: 0 AN: 39202

American (AMR) AF: 0.00 AC: 0 AN: 14478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3348

East Asian (EAS) AF: 0.00 AC: 0 AN: 4960

South Asian (SAS) AF: 0.00 AC: 0 AN: 4548

European-Finnish (FIN) AF: 0.000116 AC: 1 AN: 8602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65394

Other (OTH) AF: 0.00 AC: 0 AN: 1954

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.14
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11299077; hg19: chr18-21123536;