18-23524007-T-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMC1	NM_013326.5	c.962-123T>G		intron_variant	Intron 10 of 19	ENST00000269221.8	NP_037458.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMC1	ENST00000269221.8	c.962-123T>G		intron_variant	Intron 10 of 19	1	NM_013326.5	ENSP00000269221.2
RMC1	ENST00000590868.5	c.818-123T>G		intron_variant	Intron 8 of 17	2		ENSP00000467007.1
RMC1	ENST00000615148.5	c.962-123T>G		intron_variant	Intron 10 of 19	5		ENSP00000482573.2
RMC1	ENST00000589215.5	n.*619-123T>G		intron_variant	Intron 9 of 18	2		ENSP00000467852.1

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

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.529

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.471

Gnomad4 SAS exome AF: 0.407

Gnomad4 FIN exome AF: 0.485

Gnomad4 NFE exome AF: 0.448

Gnomad4 OTH exome AF: 0.402

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

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.273

Gnomad4 EAS AF: 0.423

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.508

Gnomad4 NFE AF: 0.444

Gnomad4 OTH AF: 0.334

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.64

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