rs143656971

Variant names:

• chr18-23561451-G-A
• rs143656971
• NM_000271.5:c.540C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-23561451-G-A
• chr18-23561451-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000271.5(NPC1):​c.540C>T​(p.Asp180Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,120 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (20 hom.)
• Consequence: NPC1 NM_000271.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.82
• Publications: 7 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]

NPC1 Gene-Disease associations (from GenCC):

• Niemann-Pick disease, type C1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, G2P
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 18-23561451-G-A is Benign according to our data. Variant chr18-23561451-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 471944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00288 (438/152282) while in subpopulation AMR AF = 0.00837 (128/15292). AF 95% confidence interval is 0.00719. There are 3 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.540C>T	p.Asp180Asp	synonymous	Exon 5 of 25	NP_000262.2	O15118-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	ENST00000269228.10	TSL:1 MANE Select	c.540C>T	p.Asp180Asp	synonymous	Exon 5 of 25	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.540C>T	p.Asp180Asp	synonymous	Exon 5 of 25	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.540C>T	p.Asp180Asp	synonymous	Exon 5 of 25	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 436 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00469 AC: 1179 AN: 251468 AF XY: 0.00361

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.0226

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00210 AC: 3070 AN: 1461838 Hom.: 20 Cov.: 32 AF XY: 0.00201 AC XY: 1463 AN XY: 727216

African (AFR) AF: 0.000836 AC: 28 AN: 33478

American (AMR) AF: 0.0201 AC: 901 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00313 AC: 167 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00166 AC: 1844 AN: 1111960

Other (OTH) AF: 0.00152 AC: 92 AN: 60396

GnomAD4 genome AF: 0.00288 AC: 438 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74450

African (AFR) AF: 0.00164 AC: 68 AN: 41550

American (AMR) AF: 0.00837 AC: 128 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00284 Hom.: 7

Bravo AF: 0.00317

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Niemann-Pick disease, type C1 (5)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.10
DANN	Benign	0.51
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs143656971; hg19: chr18-21141415; COSMIC: COSV52579441; COSMIC: COSV52579441;