Genetic Variant NM_018298.11:c.1460G>T (chr1-85021137-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

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

The NM_018298.11(MCOLN3):c.1460G>T(p.Ser487Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,612,712 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MCOLN3
NM_018298.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.21

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 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, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCOLN3	NM_018298.11 link	c.1460G>T	p.Ser487Ile	missense_variant	Exon 12 of 13	ENST00000370589.7	NP_060768.8	Q8TDD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MCOLN3	ENST00000370589.7 link	c.1460G>T	p.Ser487Ile	missense_variant	Exon 12 of 13	1	NM_018298.11	ENSP00000359621.1	Q8TDD5-1
MCOLN3	ENST00000341115.8 link	c.1292G>T	p.Ser431Ile	missense_variant	Exon 11 of 12	2		ENSP00000342698.3	Q8TDD5-2
DNAI3	ENST00000370596.5 link	c.-15+21799C>A		intron_variant	Intron 1 of 21	5		ENSP00000359628.1	Q8IWG1-2
MCOLN3	ENST00000474447.1 link	n.1485G>T		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250794

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135556

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460564

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726636

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1460G>T (p.S487I) alteration is located in exon 12 (coding exon 11) of the MCOLN3 gene. This alteration results from a G to T substitution at nucleotide position 1460, causing the serine (S) at amino acid position 487 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

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Uncertain

0.46

Sift

Benign

0.056

T;D

Sift4G

Uncertain

0.057

T;T

Polyphen

0.96

D;D

Vest4

0.82

MVP

0.89

MPC

0.39

ClinPred

0.95

GERP RS

5.9

Varity_R

0.66

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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