18-23515960-G-A

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.513G>A(p.Thr171=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,614,020 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: RMC1 NM_013326.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.80

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=-0.67).
• BP6: Variant 18-23515960-G-A is Benign according to our data. Variant chr18-23515960-G-A is described in ClinVar as [Benign]. Clinvar id is 786337.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1763/152126) while in subpopulation AFR AF= 0.0407 (1687/41484). AF 95% confidence interval is 0.0391. There are 37 homozygotes in gnomad4. There are 823 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1758 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RMC1	NM_013326.5	c.513G>A	p.Thr171=	synonymous_variant	6/20	ENST00000269221.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RMC1	ENST00000269221.8	c.513G>A	p.Thr171=	synonymous_variant	6/20	1	NM_013326.5	P1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1758 AN: 152008 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00298 AC: 749 AN: 251486 Hom.: 14 AF XY: 0.00222 AC XY: 302 AN XY: 135912

Gnomad AFR exome AF: 0.0403

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00109 AC: 1595 AN: 1461894 Hom.: 24 Cov.: 31 AF XY: 0.000953 AC XY: 693 AN XY: 727248

Gnomad4 AFR exome AF: 0.0382

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.0116 AC: 1763 AN: 152126 Hom.: 37 Cov.: 32 AF XY: 0.0111 AC XY: 823 AN XY: 74362

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00598 Hom.: 5

Bravo AF: 0.0131

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

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

Jul 15, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.028
Dann	Benign	0.88

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: rs7245127; hg19: chr18-21095924;