18-23543572-TAAAAAAAAAAA-TAAAAAAAA

Variant names:

• chr18-23543572-TAAA-T
• rs11299077
• NM_000271.5:c.2131-6_2131-4delTTT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP6_Moderate BS1

The NM_000271.5(NPC1):​c.2131-6_2131-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,192,858 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0063 (0 hom.)
• Consequence: NPC1 NM_000271.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.0610

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 18-23543572-TAAA-T is Benign according to our data. Variant chr18-23543572-TAAA-T is described in ClinVar as [Benign]. Clinvar id is 282052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-23543572-TAAA-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00632 (6634/1049272) while in subpopulation AFR AF= 0.0166 (387/23304). AF 95% confidence interval is 0.0152. There are 0 homozygotes in gnomad4_exome. There are 3235 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.2131-6_2131-4delTTT		splice_region_variant, intron_variant	Intron 13 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.2131-6_2131-4delTTT		splice_region_variant, intron_variant	Intron 13 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1207-6_1207-4delTTT		splice_region_variant, intron_variant	Intron 6 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.2045-6_2045-4delTTT		splice_region_variant, intron_variant	Intron 11 of 15	2

Frequencies

GnomAD3 genomes AF: 0.000390 AC: 56 AN: 143522 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000208

Gnomad ASJ AF: 0.000299

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000612

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00802 AC: 1389 AN: 173230 Hom.: 0 AF XY: 0.00747 AC XY: 713 AN XY: 95426

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.0154

Gnomad SAS exome AF: 0.00904

Gnomad FIN exome AF: 0.00618

Gnomad NFE exome AF: 0.00512

Gnomad OTH exome AF: 0.00840

GnomAD4 exome AF: 0.00632 AC: 6634 AN: 1049272 Hom.: 0 AF XY: 0.00603 AC XY: 3235 AN XY: 536266

Gnomad4 AFR exome AF: 0.0166

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.00296

Gnomad4 EAS exome AF: 0.00926

Gnomad4 SAS exome AF: 0.00667

Gnomad4 FIN exome AF: 0.00317

Gnomad4 NFE exome AF: 0.00590

Gnomad4 OTH exome AF: 0.00621

GnomAD4 genome AF: 0.000390 AC: 56 AN: 143586 Hom.: 0 Cov.: 0 AF XY: 0.000460 AC XY: 32 AN XY: 69500

Gnomad4 AFR AF: 0.000970

Gnomad4 AMR AF: 0.000207

Gnomad4 ASJ AF: 0.000299

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00116

Gnomad4 NFE AF: 0.0000612

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 23, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NPC1-related disorder Benign:1

May 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;