1-85021250-C-G

Variant names:

• chr1-85021250-C-G
• rs753229458
• NM_018298.11:c.1347G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_018298.11(MCOLN3):​c.1347G>C​(p.Glu449Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCOLN3 NM_018298.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

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]

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a mutagenesis_site Abolishes channel activity. (size 0) in uniprot entity MCLN3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCOLN3	NM_018298.11	c.1347G>C	p.Glu449Asp	missense_variant	Exon 12 of 13	ENST00000370589.7	NP_060768.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCOLN3	ENST00000370589.7	c.1347G>C	p.Glu449Asp	missense_variant	Exon 12 of 13	1	NM_018298.11	ENSP00000359621.1
MCOLN3	ENST00000341115.8	c.1179G>C	p.Glu393Asp	missense_variant	Exon 11 of 12	2		ENSP00000342698.3
DNAI3	ENST00000370596.5	c.-15+21912C>G		intron_variant	Intron 1 of 21	5		ENSP00000359628.1
MCOLN3	ENST00000474447.1	n.1372G>C		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249958 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135006

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1347G>C (p.E449D) alteration is located in exon 12 (coding exon 11) of the MCOLN3 gene. This alteration results from a G to C substitution at nucleotide position 1347, causing the glutamic acid (E) at amino acid position 449 to be replaced by an aspartic acid (D). 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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.68		Gain of helix (P = 0.2059);.;
MVP		0.86
MPC		0.35
ClinPred		0.95	D
GERP RS		3.8
Varity_R		0.87
gMVP		0.92

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

Other links and lift over

dbSNP: rs753229458; hg19: chr1-85486933;