18-23531868-A-G

Variant names:

• chr18-23531868-A-G
• rs886053664
• NM_000271.5:c.*334T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000271.5(NPC1):​c.*334T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NPC1 NM_000271.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.327
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.*334T>C		3_prime_UTR_variant	Exon 25 of 25	ENST00000269228.10	NP_000262.2
RMC1	NM_013326.5	c.*164A>G		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.*334T>C		3_prime_UTR_variant	Exon 25 of 25	1	NM_000271.5	ENSP00000269228.4
RMC1	ENST00000269221.8	c.*164A>G		downstream_gene_variant		1	NM_013326.5	ENSP00000269221.2
RMC1	ENST00000590868.5	c.*164A>G		downstream_gene_variant		2		ENSP00000467007.1
RMC1	ENST00000615148.5	c.*184A>G		downstream_gene_variant		5		ENSP00000482573.2
RMC1	ENST00000589215.5	n.*1671A>G		downstream_gene_variant		2		ENSP00000467852.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151830 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1296610 Hom.: 0 Cov.: 31 AF XY: 0.00000158 AC XY: 1 AN XY: 631436

African (AFR) AF: 0.00 AC: 0 AN: 28446

American (AMR) AF: 0.00 AC: 0 AN: 20638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19246

East Asian (EAS) AF: 0.00 AC: 0 AN: 35148

South Asian (SAS) AF: 0.00 AC: 0 AN: 63084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3672

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1040738

Other (OTH) AF: 0.00 AC: 0 AN: 53914

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151830 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74110

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

African (AFR) AF: 0.00 AC: 0 AN: 41340

American (AMR) AF: 0.00 AC: 0 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67944

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.74
DANN	Benign	0.48
PhyloP100		-0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886053664; hg19: chr18-21111832;