18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAA

Position:

• chr18-23543572-TAAAAAAAAAAA-TAAAAAAAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_000271.5(NPC1):​c.2131-4_2131-3insT variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:4
• Conservation: PhyloP100: -0.485

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 18-23543572-T-TA is Benign according to our data. Variant chr18-23543572-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 558884.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0118 (12437/1058326) while in subpopulation NFE AF= 0.014 (10876/776192). AF 95% confidence interval is 0.0138. There are 0 homozygotes in gnomad4_exome. There are 5971 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.2131-4_2131-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.2131-4_2131-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.1209-4_1209-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2
NPC1	ENST00000540608.5	n.2045-4_2045-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.00573 AC: 993 AN: 173230 Hom.: 0 AF XY: 0.00580 AC XY: 553 AN XY: 95426

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 SAS exome AF: 0.00352

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

Gnomad4 AFR exome AF: 0.00400

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00936

Gnomad4 EAS exome AF: 0.000672

Gnomad4 SAS exome AF: 0.00411

Gnomad4 FIN exome AF: 0.00748

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.00965

GnomAD4 genome AF: 0.000801 AC: 115 AN: 143642 Hom.: 0 Cov.: 0 AF XY: 0.000661 AC XY: 46 AN XY: 69540

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.000691

Gnomad4 ASJ AF: 0.000597

Gnomad4 EAS AF: 0.000403

Gnomad4 SAS AF: 0.000220

Gnomad4 FIN AF: 0.00105

Gnomad4 NFE AF: 0.000596

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: no assertion criteria provided

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2017	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs11299077; hg19: chr18-21123536;