18-23530033-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_013326.5(RMC1):c.1500C>T(p.Tyr500=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00647 in 1,613,348 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0059 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (60 hom.)
• Consequence: RMC1 NM_013326.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 18-23530033-C-T is Benign according to our data. Variant chr18-23530033-C-T is described in ClinVar as [Benign]. Clinvar id is 781357.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00653 (9542/1461044) while in subpopulation MID AF= 0.0246 (142/5766). AF 95% confidence interval is 0.0213. There are 60 homozygotes in gnomad4_exome. There are 5038 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 898 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RMC1	NM_013326.5	c.1500C>T	p.Tyr500=	synonymous_variant	17/20	ENST00000269221.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RMC1	ENST00000269221.8	c.1500C>T	p.Tyr500=	synonymous_variant	17/20	1	NM_013326.5	P1

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 898 AN: 152186 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00827 AC: 2080 AN: 251402 Hom.: 15 AF XY: 0.00896 AC XY: 1218 AN XY: 135880

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0141

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.00718

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00653 AC: 9542 AN: 1461044 Hom.: 60 Cov.: 32 AF XY: 0.00693 AC XY: 5038 AN XY: 726896

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.0219

Gnomad4 NFE exome AF: 0.00531

Gnomad4 OTH exome AF: 0.00827

GnomAD4 genome AF: 0.00592 AC: 902 AN: 152304 Hom.: 3 Cov.: 32 AF XY: 0.00679 AC XY: 506 AN XY: 74474

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0216

Gnomad4 NFE AF: 0.00609

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00669 Hom.: 9

Bravo AF: 0.00419

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00796

EpiControl AF: 0.00723

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	6.3
Dann	Benign	0.67

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: rs34136453; hg19: chr18-21109997;