Variant 1-85034227-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018298.11(MCOLN3):c.421G>A(p.Val141Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,614,120 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000095 ( 1 hom. )

Consequence

MCOLN3
NM_018298.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.422

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030088633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCOLN3	NM_018298.11 linkuse as main transcript	c.421G>A	p.Val141Ile	missense_variant	4/13	ENST00000370589.7	NP_060768.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCOLN3	ENST00000370589.7 linkuse as main transcript	c.421G>A	p.Val141Ile	missense_variant	4/13	1	NM_018298.11	ENSP00000359621	P1	Q8TDD5-1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251412

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000951

AC:

139

AN:

1461842

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000296

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000915

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000347

Hom.:

Bravo

AF:

0.000261

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000239

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Jan 24, 2024

The c.421G>A (p.V141I) alteration is located in exon 4 (coding exon 3) of the MCOLN3 gene. This alteration results from a G to A substitution at nucleotide position 421, causing the valine (V) at amino acid position 141 to be replaced by an isoleucine (I). 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

0.083

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.030

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.;.

MutationTaster

Benign

0.60

D;D;D;N;N;D

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.010

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.92

T;T;T

Sift4G

Benign

0.73

T;T;T

Polyphen

0.96

D;D;P

Vest4

0.14

MVP

0.12

MPC

0.049

ClinPred

0.022

GERP RS

3.9

Varity_R

0.14

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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