18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000271.5(NPC1):​c.2131-4dupT 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 0)
  • Exomes 𝑓: 0.012 (0 hom.)
• Consequence: NPC1 NM_000271.5 splice_region, intron
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:4
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 18-23543572-T-TA is Benign according to our data. Variant chr18-23543572-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 558884.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2131-4dupT		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.2131-4_2131-3insT		splice_region intron	N/A	ENSP00000269228.4
	NPC1	ENST00000591051.1	TSL:2	c.1207-4_1207-3insT		splice_region intron	N/A	ENSP00000467636.1
	NPC1	ENST00000540608.5	TSL:2	n.2045-4_2045-3insT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000787 AC: 113 AN: 143578 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000691

Gnomad ASJ AF: 0.000597

Gnomad EAS AF: 0.000402

Gnomad SAS AF: 0.000219

Gnomad FIN AF: 0.00105

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.000596

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00573 AC: 993 AN: 173230 AF XY: 0.00580

Gnomad AFR exome AF: 0.00255

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00657

Gnomad EAS exome AF: 0.00116

Gnomad FIN exome AF: 0.00599

Gnomad NFE exome AF: 0.00772

Gnomad OTH exome AF: 0.00817

GnomAD4 exome AF: 0.0118 AC: 12437 AN: 1058326 Hom.: 0 Cov.: 0 AF XY: 0.0110 AC XY: 5971 AN XY: 540836

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

African (AFR) AF: 0.00400 AC: 95 AN: 23770

American (AMR) AF: 0.00411 AC: 155 AN: 37706

Ashkenazi Jewish (ASJ) AF: 0.00936 AC: 210 AN: 22444

East Asian (EAS) AF: 0.000672 AC: 24 AN: 35720

South Asian (SAS) AF: 0.00411 AC: 294 AN: 71510

European-Finnish (FIN) AF: 0.00748 AC: 299 AN: 39958

Middle Eastern (MID) AF: 0.00790 AC: 37 AN: 4684

European-Non Finnish (NFE) AF: 0.0140 AC: 10876 AN: 776192

Other (OTH) AF: 0.00965 AC: 447 AN: 46342

⚠️ 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: 0.000801 AC: 115 AN: 143642 Hom.: 0 Cov.: 0 AF XY: 0.000661 AC XY: 46 AN XY: 69540

African (AFR) AF: 0.00130 AC: 51 AN: 39202

American (AMR) AF: 0.000691 AC: 10 AN: 14480

Ashkenazi Jewish (ASJ) AF: 0.000597 AC: 2 AN: 3348

East Asian (EAS) AF: 0.000403 AC: 2 AN: 4960

South Asian (SAS) AF: 0.000220 AC: 1 AN: 4546

European-Finnish (FIN) AF: 0.00105 AC: 9 AN: 8602

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.000596 AC: 39 AN: 65396

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

Alfa AF: 0.00930 Hom.: 572

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV52583987; COSMIC: COSV52583987;