NM_000271.5:c.2131-5_2131-4delTT

Variant names:

• chr18-23543572-TAA-T
• rs11299077
• NM_000271.5:c.2131-5_2131-4delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000271.5(NPC1):​c.2131-5_2131-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,160,146 control chromosomes in the GnomAD database, including 51 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (41 hom., cov: 0)
  • Exomes 𝑓: 0.15 (10 hom.)
• Consequence: NPC1 NM_000271.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0610
• 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, 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 -16 ACMG points.

• BP6: Variant 18-23543572-TAA-T is Benign according to our data. Variant chr18-23543572-TAA-T is described in ClinVar as Benign. ClinVar VariationId is 522212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0161 (2304/143504) while in subpopulation AFR AF = 0.0426 (1667/39156). AF 95% confidence interval is 0.0409. There are 41 homozygotes in GnomAd4. There are 1125 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

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

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	ENST00000269228.10	TSL:1 MANE Select	c.2131-5_2131-4delTT		splice_region intron	N/A	ENSP00000269228.4
	NPC1	ENST00000591051.1	TSL:2	c.1207-5_1207-4delTT		splice_region intron	N/A	ENSP00000467636.1
	NPC1	ENST00000540608.5	TSL:2	n.2045-5_2045-4delTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2282 AN: 143442 Hom.: 39 Cov.: 0

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00179

Gnomad EAS AF: 0.0284

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.00271

Gnomad OTH AF: 0.0145

GnomAD2 exomes AF: 0.246 AC: 42576 AN: 173230 AF XY: 0.244

Gnomad AFR exome AF: 0.382

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.398

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.153 AC: 156025 AN: 1016642 Hom.: 10 AF XY: 0.157 AC XY: 81157 AN XY: 518502

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

African (AFR) AF: 0.309 AC: 6909 AN: 22366

American (AMR) AF: 0.270 AC: 9636 AN: 35724

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 2872 AN: 21480

East Asian (EAS) AF: 0.375 AC: 11678 AN: 31106

South Asian (SAS) AF: 0.243 AC: 16227 AN: 66868

European-Finnish (FIN) AF: 0.145 AC: 5542 AN: 38166

Middle Eastern (MID) AF: 0.156 AC: 692 AN: 4432

European-Non Finnish (NFE) AF: 0.127 AC: 95292 AN: 752312

Other (OTH) AF: 0.162 AC: 7177 AN: 44188

⚠️ 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: 0.0161 AC: 2304 AN: 143504 Hom.: 41 Cov.: 0 AF XY: 0.0162 AC XY: 1125 AN XY: 69456

African (AFR) AF: 0.0426 AC: 1667 AN: 39156

American (AMR) AF: 0.00830 AC: 120 AN: 14464

Ashkenazi Jewish (ASJ) AF: 0.00179 AC: 6 AN: 3348

East Asian (EAS) AF: 0.0285 AC: 141 AN: 4950

South Asian (SAS) AF: 0.0132 AC: 60 AN: 4546

European-Finnish (FIN) AF: 0.0116 AC: 99 AN: 8556

Middle Eastern (MID) AF: 0.0141 AC: 4 AN: 284

European-Non Finnish (NFE) AF: 0.00271 AC: 177 AN: 65380

Other (OTH) AF: 0.0154 AC: 30 AN: 1950

Alfa AF: 0.0863 Hom.: 572

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Niemann-Pick disease, type C1 (4)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.061
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;