1-85029156-T-A

Position:

• chr1-85029156-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018298.11(MCOLN3):​c.782A>T​(p.Asp261Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCOLN3 NM_018298.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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]

MCOLN3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCOLN3	NM_018298.11	c.782A>T	p.Asp261Val	missense_variant	7/13	ENST00000370589.7	NP_060768.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCOLN3	ENST00000370589.7	c.782A>T	p.Asp261Val	missense_variant	7/13	1	NM_018298.11	ENSP00000359621.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2024

The c.782A>T (p.D261V) alteration is located in exon 7 (coding exon 6) of the MCOLN3 gene. This alteration results from a A to T substitution at nucleotide position 782, causing the aspartic acid (D) at amino acid position 261 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		0.50	P;B;P
Vest4		0.52
MutPred		0.50		Loss of ubiquitination at K257 (P = 0.0355);.;Loss of ubiquitination at K257 (P = 0.0355);
MVP		0.91
MPC		0.084
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.78
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-85494839;