Genetic Variant NPC1:c.2131-7_2131-4delTTTT (chr18-23543572-TAAAA-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000271.5(NPC1):c.2131-7_2131-4delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,204,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

NPC1
NM_000271.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.136

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.2131-7_2131-4delTTTT		splice_region_variant, intron_variant	Intron 13 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.2131-7_2131-4delTTTT	splice_region_variant, intron_variant	Intron 13 of 24	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.1207-7_1207-4delTTTT	splice_region_variant, intron_variant	Intron 6 of 17	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 link	n.2045-7_2045-4delTTTT	splice_region_variant, intron_variant	Intron 11 of 15	2

Frequencies

GnomAD3 genomes

AF:

0.00000696

AC:

AN:

143576

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:

0.00

Gnomad FIN

AF:

0.000116

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000219

AC:

AN:

173230

AF XY:

0.000199

show subpopulations

Gnomad AFR exome

AF:

0.0000912

Gnomad AMR exome

AF:

0.000369

Gnomad ASJ exome

AF:

0.000131

Gnomad EAS exome

AF:

0.000309

Gnomad FIN exome

AF:

0.000190

Gnomad NFE exome

AF:

0.000136

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.000375

AC:

398

AN:

1060562

Hom.:

AF XY:

0.000321

AC XY:

174

AN XY:

542036

show subpopulations

Gnomad4 AFR exome

AF:

0.000968

AC:

AN:

23756

Gnomad4 AMR exome

AF:

0.000344

AC:

AN:

37774

Gnomad4 ASJ exome

AF:

0.000178

AC:

AN:

22514

Gnomad4 EAS exome

AF:

0.000112

AC:

AN:

35714

Gnomad4 SAS exome

AF:

0.000307

AC:

AN:

71690

Gnomad4 FIN exome

AF:

0.0000499

AC:

AN:

40070

Gnomad4 NFE exome

AF:

0.000406

AC:

316

AN:

777916

Gnomad4 Remaining exome

AF:

0.000258

AC:

AN:

46436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

137

182

228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000696

AC:

AN:

143640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69540

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.000116

AC:

0.000116252

AN:

0.000116252

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Genomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=94/6

polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over