rs61731962

Positions:

• chr18-23556269-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000271.5(NPC1):​c.1300C>T​(p.Pro434Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00221 in 1,614,096 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P434L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.012 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (44 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.36

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000271.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-23556268-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429322.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01101315).
• BP6: Variant 18-23556269-G-A is Benign according to our data. Variant chr18-23556269-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23556269-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1807/152242) while in subpopulation AFR AF= 0.0421 (1749/41532). AF 95% confidence interval is 0.0405. There are 25 homozygotes in gnomad4. There are 809 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.1300C>T	p.Pro434Ser	missense_variant	8/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.1300C>T	p.Pro434Ser	missense_variant	8/25	1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.583C>T	p.Pro195Ser	missense_variant	3/18	2
NPC1	ENST00000540608.5	n.1214C>T		non_coding_transcript_exon_variant	6/16	2

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1805 AN: 152124 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

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: 0.00431

GnomAD3 exomes AF: 0.00329 AC: 827 AN: 251402 Hom.: 16 AF XY: 0.00227 AC XY: 308 AN XY: 135884

Gnomad AFR exome AF: 0.0469

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00120 AC: 1757 AN: 1461854 Hom.: 44 Cov.: 31 AF XY: 0.000978 AC XY: 711 AN XY: 727226

Gnomad4 AFR exome AF: 0.0452

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.0119 AC: 1807 AN: 152242 Hom.: 25 Cov.: 32 AF XY: 0.0109 AC XY: 809 AN XY: 74420

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00216 Hom.: 12

Bravo AF: 0.0135

ESP6500AA AF: 0.0429 AC: 189

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00387 AC: 470

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	This variant is associated with the following publications: (PMID: 12955717) -

Niemann-Pick disease, type C1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.73	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.39
Sift	Benign	0.041	D
Sift4G	Uncertain	0.032	D
Polyphen		0.0010	B
Vest4		0.56
MVP		0.80
MPC		0.33
ClinPred		0.016	T
GERP RS		4.6
Varity_R		0.34
gMVP		0.86

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

Other links and lift over

dbSNP: rs61731962; hg19: chr18-21136233;