18-23543572-TAAAAAAAAAAA-TAAAAAAAAAA

Variant names:

• chr18-23543572-TA-T
• rs11299077
• NM_000271.5:c.2131-4delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000271.5(NPC1):​c.2131-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (30714 hom., cov: 0)
  • Exomes 𝑓: 0.44 (4735 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPC1 NM_000271.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.485
• 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-TA-T is Benign according to our data. Variant chr18-23543572-TA-T is described in ClinVar as Benign. ClinVar VariationId is 403254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

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.2131-4delT		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.2131-4delT		splice_region intron	N/A	ENSP00000269228.4
	NPC1	ENST00000591051.1	TSL:2	c.1207-4delT		splice_region intron	N/A	ENSP00000467636.1
	NPC1	ENST00000540608.5	TSL:2	n.2045-4delT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.646 AC: 92677 AN: 143532 Hom.: 30711 Cov.: 0

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.632

GnomAD2 exomes AF: 0.461 AC: 79877 AN: 173230 AF XY: 0.461

Gnomad AFR exome AF: 0.466

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.475

Gnomad FIN exome AF: 0.456

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.459

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.440 AC: 460275 AN: 1046340 Hom.: 4735 Cov.: 0 AF XY: 0.442 AC XY: 236417 AN XY: 534492

African (AFR) AF: 0.477 AC: 11312 AN: 23732

American (AMR) AF: 0.462 AC: 17376 AN: 37592

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 9917 AN: 21946

East Asian (EAS) AF: 0.490 AC: 17477 AN: 35692

South Asian (SAS) AF: 0.468 AC: 33280 AN: 71128

European-Finnish (FIN) AF: 0.450 AC: 17575 AN: 39030

Middle Eastern (MID) AF: 0.468 AC: 2168 AN: 4628

European-Non Finnish (NFE) AF: 0.431 AC: 330705 AN: 766824

Other (OTH) AF: 0.447 AC: 20465 AN: 45768

GnomAD4 genome AF: 0.646 AC: 92715 AN: 143600 Hom.: 30714 Cov.: 0 AF XY: 0.651 AC XY: 45271 AN XY: 69538

African (AFR) AF: 0.823 AC: 32255 AN: 39184

American (AMR) AF: 0.686 AC: 9928 AN: 14480

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 1770 AN: 3346

East Asian (EAS) AF: 0.892 AC: 4426 AN: 4960

South Asian (SAS) AF: 0.739 AC: 3360 AN: 4546

European-Finnish (FIN) AF: 0.535 AC: 4611 AN: 8618

Middle Eastern (MID) AF: 0.606 AC: 172 AN: 284

European-Non Finnish (NFE) AF: 0.527 AC: 34427 AN: 65360

Other (OTH) AF: 0.633 AC: 1236 AN: 1952

Alfa AF: 0.383 Hom.: 572

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Niemann-Pick disease, type C1 (7)
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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;