Genetic Variant RMC1:n.*1526delT (chr18-23531716-GT-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000589215.5(RMC1):n.*1526delT variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,770 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RMC1
ENST00000589215.5 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.442

Publications

0 publications found

Variant links:

Genes affected

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

RMC1 links:

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

NPC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.*485delA		3_prime_UTR_variant	Exon 25 of 25	ENST00000269228.10	NP_000262.2
RMC1	NM_013326.5 link	c.*19delT		3_prime_UTR_variant	Exon 20 of 20	ENST00000269221.8	NP_037458.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RMC1	ENST00000589215.5 link	n.*1526delT	non_coding_transcript_exon_variant	Exon 19 of 19	2		ENSP00000467852.1	K7EQJ3
NPC1	ENST00000269228.10 link	c.*485delA	3_prime_UTR_variant	Exon 25 of 25	1	NM_000271.5	ENSP00000269228.4	O15118-1
RMC1	ENST00000269221.8 link	c.*19delT	3_prime_UTR_variant	Exon 20 of 20	1	NM_013326.5	ENSP00000269221.2	Q96DM3
RMC1	ENST00000590868.5 link	c.*19delT	3_prime_UTR_variant	Exon 18 of 18	2		ENSP00000467007.1	K7ENL9
RMC1	ENST00000615148.5 link	c.*39delT	3_prime_UTR_variant	Exon 20 of 20	5		ENSP00000482573.2	A0A087WZD4
RMC1	ENST00000589215.5 link	n.*1526delT	3_prime_UTR_variant	Exon 19 of 19	2		ENSP00000467852.1	K7EQJ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1446770

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719086

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32510

American (AMR)

AF:

0.00

AC:

AN:

40206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25458

East Asian (EAS)

AF:

0.00

AC:

AN:

39570

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108216

Other (OTH)

AF:

0.00

AC:

AN:

59774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.44

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

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18-23531716-GTTTT-GTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over