Genetic Variant NPC1:c.*328A>G (chr18-23531874-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000271.5(NPC1):c.*328A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,446,424 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

NPC1
NM_000271.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

Publications

1 publications found

Variant links:

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 links:

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

RMC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.*328A>G		3_prime_UTR_variant	Exon 25 of 25	ENST00000269228.10	NP_000262.2
RMC1	NM_013326.5 link	c.*170T>C		downstream_gene_variant		ENST00000269221.8	NP_037458.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.*328A>G	3_prime_UTR_variant	Exon 25 of 25	1	NM_000271.5	ENSP00000269228.4	O15118-1
RMC1	ENST00000269221.8 link	c.*170T>C	downstream_gene_variant		1	NM_013326.5	ENSP00000269221.2	Q96DM3
RMC1	ENST00000590868.5 link	c.*170T>C	downstream_gene_variant		2		ENSP00000467007.1	K7ENL9
RMC1	ENST00000615148.5 link	c.*190T>C	downstream_gene_variant		5		ENSP00000482573.2	A0A087WZD4
RMC1	ENST00000589215.5 link	n.*1677T>C	downstream_gene_variant		2		ENSP00000467852.1	K7EQJ3

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151706

Hom.:

Cov.:

show subpopulations

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:

0.000635

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1294600

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

630104

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28400

American (AMR)

AF:

0.00

AC:

AN:

20508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19180

East Asian (EAS)

AF:

0.00

AC:

AN:

35110

South Asian (SAS)

AF:

0.000334

AC:

AN:

62838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3638

European-Non Finnish (NFE)

AF:

0.00000289

AC:

AN:

1039628

Other (OTH)

AF:

0.00

AC:

AN:

53844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151824

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000635

AC:

AN:

4722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67950

Other (OTH)

AF:

0.00

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

7.7

(source)

DANN

Benign

0.62

PhyloP100

1.1

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

Publications

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18-23531874-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over