chr18-23524007-T-G

Variant names:

• chr18-23524007-T-G
• rs891386
• NM_013326.5:c.962-123T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013326.5(RMC1):​c.962-123T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 1,090,348 control chromosomes in the GnomAD database, including 103,464 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (11436 hom., cov: 32)
  • Exomes 𝑓: 0.44 (92028 hom.)
• Consequence: RMC1 NM_013326.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.571
• Publications: 16 publications found

Genes affected

RMC1 (HGNC:24326): (regulator of MON1-CCZ1) This gene encodes a colon cancer associated protein. [provided by RefSeq, Jan 2013]

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013326.5. 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
	RMC1	NM_013326.5	MANE Select	c.962-123T>G		intron	N/A	NP_037458.3
	RMC1	NM_001318709.1		c.818-123T>G		intron	N/A	NP_001305638.1	B7Z3Q1
	RMC1	NM_001276342.1		c.818-123T>G		intron	N/A	NP_001263271.1	B7Z2Y1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMC1	ENST00000269221.8	TSL:1 MANE Select	c.962-123T>G		intron	N/A	ENSP00000269221.2	Q96DM3
	RMC1	ENST00000590868.5	TSL:2	c.818-123T>G		intron	N/A	ENSP00000467007.1	K7ENL9
	RMC1	ENST00000615148.5	TSL:5	c.962-123T>G		intron	N/A	ENSP00000482573.2	A0A087WZD4

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55137 AN: 151988 Hom.: 11426 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.329

GnomAD4 exome AF: 0.437 AC: 409564 AN: 938240 Hom.: 92028 AF XY: 0.434 AC XY: 208996 AN XY: 481736

African (AFR) AF: 0.140 AC: 3320 AN: 23666

American (AMR) AF: 0.529 AC: 20275 AN: 38354

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 5529 AN: 20322

East Asian (EAS) AF: 0.471 AC: 17351 AN: 36822

South Asian (SAS) AF: 0.407 AC: 27562 AN: 67778

European-Finnish (FIN) AF: 0.485 AC: 21612 AN: 44516

Middle Eastern (MID) AF: 0.245 AC: 1129 AN: 4610

European-Non Finnish (NFE) AF: 0.448 AC: 295497 AN: 659140

Other (OTH) AF: 0.402 AC: 17289 AN: 43032

GnomAD4 genome AF: 0.363 AC: 55173 AN: 152108 Hom.: 11436 Cov.: 32 AF XY: 0.365 AC XY: 27163 AN XY: 74348

African (AFR) AF: 0.154 AC: 6380 AN: 41512

American (AMR) AF: 0.463 AC: 7068 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 946 AN: 3466

East Asian (EAS) AF: 0.423 AC: 2180 AN: 5156

South Asian (SAS) AF: 0.392 AC: 1889 AN: 4818

European-Finnish (FIN) AF: 0.508 AC: 5375 AN: 10576

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.444 AC: 30174 AN: 67990

Other (OTH) AF: 0.334 AC: 705 AN: 2110

Alfa AF: 0.338 Hom.: 1509

Bravo AF: 0.352

Asia WGS AF: 0.418 AC: 1453 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.64
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

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: rs891386; hg19: chr18-21103971; COSMIC: COSV52570403; COSMIC: COSV52570403;