18-23544943-ACCCC-ACCCCCCCC

Variant names:

• chr18-23544943-A-ACCCC
• rs3837910
• NM_000271.5:c.1947+13_1947+16dupGGGG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000271.5(NPC1):​c.1947+13_1947+16dupGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (324 hom., cov: 0)
  • Exomes 𝑓: 0.022 (244 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.952
• Publications: 3 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 -12 ACMG points.

• BP6: Variant 18-23544943-A-ACCCC is Benign according to our data. Variant chr18-23544943-A-ACCCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 324 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.1947+13_1947+16dupGGGG		intron	N/A	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.1947+16_1947+17insGGGG		intron	N/A	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.1998+16_1998+17insGGGG		intron	N/A	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.1947+16_1947+17insGGGG		intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 3065 AN: 103412 Hom.: 324 Cov.: 0

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.0455

Gnomad AMR AF: 0.0638

Gnomad ASJ AF: 0.00898

Gnomad EAS AF: 0.0761

Gnomad SAS AF: 0.0344

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0300

GnomAD4 exome AF: 0.0216 AC: 19340 AN: 894194 Hom.: 244 Cov.: 19 AF XY: 0.0226 AC XY: 10333 AN XY: 456352

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00790 AC: 200 AN: 25330

American (AMR) AF: 0.0441 AC: 1532 AN: 34772

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 270 AN: 20244

East Asian (EAS) AF: 0.0322 AC: 812 AN: 25234

South Asian (SAS) AF: 0.0446 AC: 2978 AN: 66818

European-Finnish (FIN) AF: 0.0351 AC: 1340 AN: 38144

Middle Eastern (MID) AF: 0.00885 AC: 37 AN: 4182

European-Non Finnish (NFE) AF: 0.0177 AC: 11359 AN: 640460

Other (OTH) AF: 0.0208 AC: 812 AN: 39010

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0296 AC: 3064 AN: 103458 Hom.: 324 Cov.: 0 AF XY: 0.0294 AC XY: 1437 AN XY: 48950

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0286 AC: 888 AN: 31042

American (AMR) AF: 0.0638 AC: 552 AN: 8654

Ashkenazi Jewish (ASJ) AF: 0.00898 AC: 25 AN: 2784

East Asian (EAS) AF: 0.0763 AC: 265 AN: 3474

South Asian (SAS) AF: 0.0343 AC: 102 AN: 2976

European-Finnish (FIN) AF: 0.0274 AC: 132 AN: 4826

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.0217 AC: 1027 AN: 47408

Other (OTH) AF: 0.0299 AC: 43 AN: 1440

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0317 Hom.: 365

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Niemann-Pick disease, type C1 (4)
-	-	4	not specified (4)
-	-	1	not provided (1)
-	-	1	NPC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3837910; hg19: chr18-21124907; COSMIC: COSV105007429; COSMIC: COSV105007429;