rs145236115

Variant names:

• chr18-23531886-CCTTTACA-C
• rs145236115
• NM_000271.5:c.*309_*315delTGTAAAG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000271.5(NPC1):​c.*309_*315delTGTAAAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,443,394 control chromosomes in the GnomAD database, including 74 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0064 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (65 hom.)
• Consequence: NPC1 NM_000271.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.86
• Publications: 0 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]

RMC1 (HGNC:24326): (regulator of MON1-CCZ1) This gene encodes a colon cancer associated protein. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 18-23531886-CCTTTACA-C is Benign according to our data. Variant chr18-23531886-CCTTTACA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 326243.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00641 (970/151368) while in subpopulation NFE AF = 0.0091 (618/67926). AF 95% confidence interval is 0.0085. There are 9 homozygotes in GnomAd4. There are 496 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.*309_*315delTGTAAAG		3_prime_UTR_variant	Exon 25 of 25	ENST00000269228.10	NP_000262.2
RMC1	NM_013326.5	c.*183_*189delCTTTACA		downstream_gene_variant		ENST00000269221.8	NP_037458.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.*309_*315delTGTAAAG		3_prime_UTR_variant	Exon 25 of 25	1	NM_000271.5	ENSP00000269228.4
RMC1	ENST00000269221.8	c.*183_*189delCTTTACA		downstream_gene_variant		1	NM_013326.5	ENSP00000269221.2
RMC1	ENST00000590868.5	c.*183_*189delCTTTACA		downstream_gene_variant		2		ENSP00000467007.1
RMC1	ENST00000615148.5	c.*203_*209delCTTTACA		downstream_gene_variant		5		ENSP00000482573.2
RMC1	ENST00000589215.5	n.*1690_*1696delCTTTACA		downstream_gene_variant		2		ENSP00000467852.1

Frequencies

GnomAD3 genomes AF: 0.00641 AC: 970 AN: 151252 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00238

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00385

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00911

Gnomad OTH AF: 0.00434

GnomAD4 exome AF: 0.00804 AC: 10391 AN: 1292026 Hom.: 65 AF XY: 0.00789 AC XY: 4960 AN XY: 628432

African (AFR) AF: 0.000846 AC: 24 AN: 28358

American (AMR) AF: 0.00201 AC: 41 AN: 20370

Ashkenazi Jewish (ASJ) AF: 0.000315 AC: 6 AN: 19074

East Asian (EAS) AF: 0.0000285 AC: 1 AN: 35050

South Asian (SAS) AF: 0.00452 AC: 283 AN: 62582

European-Finnish (FIN) AF: 0.0187 AC: 583 AN: 31132

Middle Eastern (MID) AF: 0.00138 AC: 5 AN: 3626

European-Non Finnish (NFE) AF: 0.00882 AC: 9153 AN: 1038102

Other (OTH) AF: 0.00549 AC: 295 AN: 53732

GnomAD4 genome AF: 0.00641 AC: 970 AN: 151368 Hom.: 9 Cov.: 32 AF XY: 0.00671 AC XY: 496 AN XY: 73876

African (AFR) AF: 0.00114 AC: 47 AN: 41202

American (AMR) AF: 0.00237 AC: 36 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00407 AC: 19 AN: 4668

European-Finnish (FIN) AF: 0.0221 AC: 231 AN: 10466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00910 AC: 618 AN: 67926

Other (OTH) AF: 0.00429 AC: 9 AN: 2096

Alfa AF: 0.00923 Hom.: 0

Bravo AF: 0.00455

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPC1: BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Niemann-Pick disease, type C Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145236115; hg19: chr18-21111850;