rs797044818

Positions:

chr19-7530332-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_020533.3(MCOLN1):c.1406A>G(p.Asn469Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MCOLN1
NM_020533.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3O:1

Conservation

PhyloP100: 8.92

Variant links:

Genes affected

MCOLN1 (HGNC:13356): (mucolipin TRP cation channel 1) This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV. [provided by RefSeq, Oct 2009]

MCOLN1 links:

MCOLN1 (HGNC:):

MCOLN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 19-7530332-A-G is Pathogenic according to our data. Variant chr19-7530332-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208023.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCOLN1	NM_020533.3 linkuse as main transcript	c.1406A>G	p.Asn469Ser	missense_variant	12/14	ENST00000264079.11	NP_065394.1	Q9GZU1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCOLN1	ENST00000264079.11 linkuse as main transcript	c.1406A>G	p.Asn469Ser	missense_variant	12/14	1	NM_020533.3	ENSP00000264079.5		Q9GZU1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461424

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000378

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mucolipidosis type IV

Pathogenic:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	Base pair transition creates a new preferred splice acceptor site that results in a frameshift. Causes atypical MLIV, in which affected persons walk independently and have better communicative skills. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 25, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2022	Variant summary: MCOLN1 c.1406A>G (p.Asn469Ser, legacy name: g.9107A>G) results in a conservative amino acid change located in the polycystin cation channel, PKD1/PKD2 domain (IPR013122) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic exonic 3' acceptor site, which if used, would result in an in-frame deletion expected to disrupt the pore architecture of the channel (e.g. Zhang_2017). However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250910 control chromosomes (gnomAD). c.1406A>G has been reported in the literature as a biallelic genotype in at least two individuals affected with Mucolipidosis Type 4 (e.g. Sun_2000). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters, including a reputable database, GeneReviews, have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

MCOLN1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2024

The MCOLN1 c.1406A>G variant is predicted to result in the amino acid substitution p.Asn469Ser. Based on available splicing prediction software, this variant is predicted to result in the creation of an alternate splice acceptor site, truncating the protein (Alamut Visual Plus v1.6.1; SpliceAI); however, prediction programs are imperfect and we cannot be certain of the biological impact of this particular variant. This variant has been reported in homozygous state as well as together with MCOLN1 nonsense variant, in at least two individuals with mucolipidosis IV (described as g.9107A>G, families 48 and 53, Sun et al. 2000. PubMed ID: 11030752; patients 15 and 23, Altarescu et al. 2002. PubMed ID: 12182165; same two patients in both publications). This variant has not been reported in a large population database, indicating this variant is rare. A different missense change impacting the same amino acid (p.Asn469Asp) has also been reported in an individual with mucolipidosis IV (Table 1: ID 4, Misko et al. 2022. PubMed ID: 35425852). The c.1406A>G (p.Asn469Ser) variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.8

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.95

MutPred

0.76

Gain of glycosylation at N469 (P = 0.0467);

MVP

0.87

MPC

2.1

ClinPred

1.0

GERP RS

5.3

Varity_R

0.87

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.89

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.89

Position offset: 1

DS_AL_spliceai

0.37

Position offset: -46

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over