rs12970899

Variant names:

• chr18-23568899-A-G
• rs12970899
• NM_000271.5:c.387T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000271.5(NPC1):​c.387T>C​(p.Tyr129Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,613,482 control chromosomes in the GnomAD database, including 20,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1617 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19011 hom.)
• Consequence: NPC1 NM_000271.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.0660
• Publications: 31 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=-0.83).
• BP6: Variant 18-23568899-A-G is Benign according to our data. Variant chr18-23568899-A-G is described in ClinVar as Benign. ClinVar VariationId is 129811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.066 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

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.387T>C	p.Tyr129Tyr	synonymous	Exon 4 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.387T>C	p.Tyr129Tyr	synonymous	Exon 4 of 25	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.387T>C	p.Tyr129Tyr	synonymous	Exon 4 of 25	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.387T>C	p.Tyr129Tyr	synonymous	Exon 4 of 25	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20273 AN: 152138 Hom.: 1619 Cov.: 32

Gnomad AFR AF: 0.0677

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.144 AC: 36100 AN: 251370 AF XY: 0.152

Gnomad AFR exome AF: 0.0666

Gnomad AMR exome AF: 0.0926

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.0157

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.156 AC: 227543 AN: 1461226 Hom.: 19011 Cov.: 32 AF XY: 0.158 AC XY: 114914 AN XY: 726988

African (AFR) AF: 0.0664 AC: 2224 AN: 33478

American (AMR) AF: 0.0984 AC: 4400 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 7111 AN: 26132

East Asian (EAS) AF: 0.0128 AC: 509 AN: 39684

South Asian (SAS) AF: 0.183 AC: 15771 AN: 86242

European-Finnish (FIN) AF: 0.144 AC: 7700 AN: 53408

Middle Eastern (MID) AF: 0.251 AC: 1443 AN: 5760

European-Non Finnish (NFE) AF: 0.161 AC: 178596 AN: 1111424

Other (OTH) AF: 0.162 AC: 9789 AN: 60376

GnomAD4 genome AF: 0.133 AC: 20266 AN: 152256 Hom.: 1617 Cov.: 32 AF XY: 0.134 AC XY: 10003 AN XY: 74442

African (AFR) AF: 0.0678 AC: 2815 AN: 41536

American (AMR) AF: 0.131 AC: 2005 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 961 AN: 3472

East Asian (EAS) AF: 0.0177 AC: 92 AN: 5192

South Asian (SAS) AF: 0.190 AC: 919 AN: 4826

European-Finnish (FIN) AF: 0.132 AC: 1397 AN: 10592

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11421 AN: 68014

Other (OTH) AF: 0.164 AC: 346 AN: 2116

Alfa AF: 0.164 Hom.: 4470

Bravo AF: 0.128

Asia WGS AF: 0.105 AC: 367 AN: 3478

EpiCase AF: 0.182

EpiControl AF: 0.180

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Niemann-Pick disease, type C1 (6)
-	-	6	not specified (6)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.1
DANN	Benign	0.36
PhyloP100		-0.066
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs12970899; hg19: chr18-21148863;