18-23524186-T-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_013326.5(RMC1):​c.1006+12T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,613,314 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

RMC1
NM_013326.5 intron

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.669
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 18-23524186-T-A is Benign according to our data. Variant chr18-23524186-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 3336056.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 142 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RMC1NM_013326.5 linkc.1006+12T>A intron_variant Intron 11 of 19 ENST00000269221.8 NP_037458.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RMC1ENST00000269221.8 linkc.1006+12T>A intron_variant Intron 11 of 19 1 NM_013326.5 ENSP00000269221.2 Q96DM3
RMC1ENST00000590868.5 linkc.862+12T>A intron_variant Intron 9 of 17 2 ENSP00000467007.1 K7ENL9
RMC1ENST00000615148.5 linkc.1006+12T>A intron_variant Intron 11 of 19 5 ENSP00000482573.2 A0A087WZD4
RMC1ENST00000589215.5 linkn.*663+12T>A intron_variant Intron 10 of 18 2 ENSP00000467852.1 K7EQJ3

Frequencies

GnomAD3 genomes
AF:
0.000933
AC:
142
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00179
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00162
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.00112
AC:
282
AN:
250856
AF XY:
0.00125
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00152
Gnomad NFE exome
AF:
0.00195
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00145
AC:
2125
AN:
1460976
Hom.:
2
Cov.:
31
AF XY:
0.00141
AC XY:
1026
AN XY:
726858
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
AC:
6
AN:
33480
Gnomad4 AMR exome
AF:
0.000134
AC:
6
AN:
44722
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26134
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39700
Gnomad4 SAS exome
AF:
0.000301
AC:
26
AN:
86256
Gnomad4 FIN exome
AF:
0.00211
AC:
111
AN:
52606
Gnomad4 NFE exome
AF:
0.00171
AC:
1904
AN:
1111922
Gnomad4 Remaining exome
AF:
0.00119
AC:
72
AN:
60388
Heterozygous variant carriers
0
111
223
334
446
557
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
62
124
186
248
310
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000932
AC:
142
AN:
152338
Hom.:
0
Cov.:
32
AF XY:
0.000792
AC XY:
59
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.000241
AC:
0.000240535
AN:
0.000240535
Gnomad4 AMR
AF:
0.000131
AC:
0.000130634
AN:
0.000130634
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00179
AC:
0.00178874
AN:
0.00178874
Gnomad4 NFE
AF:
0.00162
AC:
0.00161684
AN:
0.00161684
Gnomad4 OTH
AF:
0.000473
AC:
0.000473037
AN:
0.000473037
Heterozygous variant carriers
0
8
16
24
32
40
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00111
Hom.:
0
Bravo
AF:
0.000808

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
May 10, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: RMC1 c.1006+12T>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 282254 control chromosomes in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.1006+12T>A in individuals affected with RMC1 Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.77
CADD
Benign
2.8
DANN
Benign
0.74
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148467554; hg19: chr18-21104150; API