chr18-23530033-C-T

Variant names:

• chr18-23530033-C-T
• rs34136453
• NM_013326.5:c.1500C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_013326.5(RMC1):​c.1500C>T​(p.Tyr500Tyr) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.15
• Publications: 5 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
• 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 -21 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_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 5038 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 902 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMC1	NM_013326.5	c.1500C>T	p.Tyr500Tyr	synonymous_variant	Exon 17 of 20	ENST00000269221.8	NP_037458.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMC1	ENST00000269221.8	c.1500C>T	p.Tyr500Tyr	synonymous_variant	Exon 17 of 20	1	NM_013326.5	ENSP00000269221.2
RMC1	ENST00000590868.5	c.1356C>T	p.Tyr452Tyr	synonymous_variant	Exon 15 of 18	2		ENSP00000467007.1
RMC1	ENST00000615148.5	c.1500C>T	p.Tyr500Tyr	synonymous_variant	Exon 17 of 20	5		ENSP00000482573.2
RMC1	ENST00000589215.5	n.*1157C>T		non_coding_transcript_exon_variant	Exon 16 of 19	2		ENSP00000467852.1
RMC1	ENST00000589215.5	n.*1157C>T		3_prime_UTR_variant	Exon 16 of 19	2		ENSP00000467852.1

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

GnomAD2 exomes AF: 0.00827 AC: 2080 AN: 251402 AF XY: 0.00896

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 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

African (AFR) AF: 0.00164 AC: 55 AN: 33454

American (AMR) AF: 0.00309 AC: 138 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 479 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0134 AC: 1154 AN: 86232

European-Finnish (FIN) AF: 0.0219 AC: 1169 AN: 53416

Middle Eastern (MID) AF: 0.0246 AC: 142 AN: 5766

European-Non Finnish (NFE) AF: 0.00531 AC: 5905 AN: 1111282

Other (OTH) AF: 0.00827 AC: 499 AN: 60360

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

African (AFR) AF: 0.00132 AC: 55 AN: 41560

American (AMR) AF: 0.00379 AC: 58 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4834

European-Finnish (FIN) AF: 0.0216 AC: 229 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00609 AC: 414 AN: 68028

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00642 Hom.: 11

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.3
DANN	Benign	0.67
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

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: rs34136453; hg19: chr18-21109997;