1-85034148-T-G

Position:

• chr1-85034148-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018298.11(MCOLN3):​c.500A>C​(p.Asn167Thr) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCOLN3 NM_018298.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.670

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023114562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCOLN3	NM_018298.11	c.500A>C	p.Asn167Thr	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	c.500A>C	p.Asn167Thr	missense_variant	4/13	1	NM_018298.11	ENSP00000359621	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 12, 2021

The c.500A>C (p.N167T) alteration is located in exon 4 (coding exon 3) of the MCOLN3 gene. This alteration results from a A to C substitution at nucleotide position 500, causing the asparagine (N) at amino acid position 167 to be replaced by a threonine (T). 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	0.078
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.0
DANN	Benign	0.55
DEOGEN2	Benign	0.065	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.46	T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.81	N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.36	N;N;N
REVEL	Benign	0.026
Sift	Benign	0.79	T;T;T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.20
MutPred		0.36		Loss of sheet (P = 0.0104);.;Loss of sheet (P = 0.0104);
MVP		0.28
MPC		0.057
ClinPred		0.041	T
GERP RS		-4.7
Varity_R		0.063
gMVP		0.31

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: rs1344372711; hg19: chr1-85499831;