1-85022346-C-T

Position:

chr1-85022346-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_018298.11(MCOLN3):c.1150G>A(p.Val384Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MCOLN3
NM_018298.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.53

Variant links:

Genes affected

MCOLN3 (HGNC:13358): (mucolipin TRP cation channel 3) This gene encodes one of members of the mucolipin cation channel proteins. Mutation studies of the highly similar protein in mice have shown that the protein is found in cochlea hair cells, and mutant mice show early-onset hearing loss and balance problems. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

MCOLN3 links:

DNAI3 (HGNC:30711): (dynein axonemal intermediate chain 3) Enables Arp2/3 complex binding activity. Involved in negative regulation of Arp2/3 complex-mediated actin nucleation and negative regulation of cell migration. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DNAI3 links:

MCOLN3 (HGNC:):

MCOLN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCOLN3	NM_018298.11 linkuse as main transcript	c.1150G>A	p.Val384Met	missense_variant	10/13	ENST00000370589.7	NP_060768.8	Q8TDD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MCOLN3	ENST00000370589.7 linkuse as main transcript	c.1150G>A	p.Val384Met	missense_variant	10/13	1	NM_018298.11	ENSP00000359621.1	Q8TDD5-1
MCOLN3	ENST00000341115.8 linkuse as main transcript	c.982G>A	p.Val328Met	missense_variant	9/12	2		ENSP00000342698.3	Q8TDD5-2
DNAI3	ENST00000370596.5 linkuse as main transcript	c.-15+23008C>T		intron_variant		5		ENSP00000359628.1	Q8IWG1-2
MCOLN3	ENST00000474447.1 linkuse as main transcript	n.1175G>A		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250972

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461564

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2024

The c.1150G>A (p.V384M) alteration is located in exon 10 (coding exon 9) of the MCOLN3 gene. This alteration results from a G to A substitution at nucleotide position 1150, causing the valine (V) at amino acid position 384 to be replaced by a methionine (M). 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

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.079

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Uncertain

-0.038

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.8

D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

1.0

D;D

Vest4

0.80

MutPred

0.60

Loss of catalytic residue at V384 (P = 0.1);.;

MVP

0.91

MPC

0.32

ClinPred

0.93

GERP RS

5.7

Varity_R

0.58

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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.

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