dbSNP rs150334966: NPC1:p.Ser1004Leu (chr18-23538572-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PM1PP2PP5BP4BS1_SupportingBS2

The NM_000271.5(NPC1):c.3011C>T(p.Ser1004Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000728 in 1,614,152 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1004S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 2 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:7

Conservation

PhyloP100: 8.06

Publications

18 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 Gene-Disease associations (from GenCC):

Niemann-Pick disease, type C1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
Niemann-Pick disease type C, adult neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, juvenile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, late infantile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, severe early infantile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, severe perinatal form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000271.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 171 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 1.0917 (below the threshold of 3.09). Trascript score misZ: 1.706 (below the threshold of 3.09). GenCC associations: The gene is linked to Niemann-Pick disease, type C1, Niemann-Pick disease type C, severe early infantile neurologic onset, Niemann-Pick disease type C, late infantile neurologic onset, Niemann-Pick disease type C, adult neurologic onset, Niemann-Pick disease type C, juvenile neurologic onset, Niemann-Pick disease type C, severe perinatal form.

PP5

Variant 18-23538572-G-A is Pathogenic according to our data. Variant chr18-23538572-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 326253.

BP4

Computational evidence support a benign effect (MetaRNN=0.3705725). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000736 (1076/1461878) while in subpopulation EAS AF = 0.00448 (178/39698). AF 95% confidence interval is 0.00395. There are 2 homozygotes in GnomAdExome4. There are 532 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.3011C>T	p.Ser1004Leu	missense	Exon 20 of 25	NP_000262.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPC1	ENST00000269228.10	TSL:1 MANE Select	c.3011C>T	p.Ser1004Leu	missense	Exon 20 of 25	ENSP00000269228.4
NPC1	ENST00000897526.1		c.3062C>T	p.Ser1021Leu	missense	Exon 20 of 25	ENSP00000567585.1
NPC1	ENST00000926494.1		c.3011C>T	p.Ser1004Leu	missense	Exon 20 of 25	ENSP00000596553.1

Frequencies

GnomAD3 genomes

AF:

0.000651

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000684

AC:

172

AN:

251486

AF XY:

0.000728

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00113

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000736

AC:

1076

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000732

AC XY:

532

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00448

AC:

178

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00157

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000688

AC:

765

AN:

1112002

Other (OTH)

AF:

0.000596

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000650

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41556

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00107

AC:

AN:

68016

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000780

Hom.:

Bravo

AF:

0.000468

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000939

AC:

114

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Niemann-Pick disease, type C1 (8)

not provided (3)

Niemann-Pick disease, type C (1)

NPC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.37

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.1

PhyloP100

8.1

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.76

Sift

Benign

0.062

Sift4G

Benign

0.16

Polyphen

0.84

Vest4

0.93

MVP

0.95

MPC

0.29

ClinPred

0.17

GERP RS

5.4

Varity_R

0.49

gMVP

0.81

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over