rs139487898

Variant names:

• chr18-23527897-C-T
• rs139487898
• NM_013326.5:c.1292C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_013326.5(RMC1):​c.1292C>T​(p.Ala431Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000806 in 1,612,394 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (3 hom.)
• Consequence: RMC1 NM_013326.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 6 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022860974).
• BS2: High AC in GnomAd4 at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMC1	NM_013326.5	c.1292C>T	p.Ala431Val	missense_variant	Exon 14 of 20	ENST00000269221.8	NP_037458.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMC1	ENST00000269221.8	c.1292C>T	p.Ala431Val	missense_variant	Exon 14 of 20	1	NM_013326.5	ENSP00000269221.2
RMC1	ENST00000590868.5	c.1148C>T	p.Ala383Val	missense_variant	Exon 12 of 18	2		ENSP00000467007.1
RMC1	ENST00000615148.5	c.1292C>T	p.Ala431Val	missense_variant	Exon 14 of 20	5		ENSP00000482573.2
RMC1	ENST00000589215.5	n.*949C>T		non_coding_transcript_exon_variant	Exon 13 of 19	2		ENSP00000467852.1
RMC1	ENST00000589215.5	n.*949C>T		3_prime_UTR_variant	Exon 13 of 19	2		ENSP00000467852.1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000336 AC: 84 AN: 250280 AF XY: 0.000318

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000707

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000843 AC: 1231 AN: 1460110 Hom.: 3 Cov.: 30 AF XY: 0.000786 AC XY: 571 AN XY: 726394

African (AFR) AF: 0.0000598 AC: 2 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86146

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00108 AC: 1197 AN: 1110744

Other (OTH) AF: 0.000431 AC: 26 AN: 60340

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74450

African (AFR) AF: 0.000120 AC: 5 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000912 AC: 62 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000596 Hom.: 0

Bravo AF: 0.000382

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000873

EpiControl AF: 0.000772

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1292C>T (p.A431V) alteration is located in exon 14 (coding exon 14) of the C18orf8 gene. This alteration results from a C to T substitution at nucleotide position 1292, causing the alanine (A) at amino acid position 431 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.72
DEOGEN2	Benign	0.0076	T;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		2.4
PROVEAN	Benign	-0.48	.;N;.
REVEL	Benign	0.022
Sift	Benign	0.95	.;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.031	.;B;.
Vest4		0.25
MVP		0.17
MPC		0.38
ClinPred		0.063	T
GERP RS		3.5
Varity_R		0.023
gMVP		0.25
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139487898; hg19: chr18-21107861; COSMIC: COSV52575111; COSMIC: COSV52575111;