19-7522779-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_020533.3(MCOLN1):c.29C>T(p.Ser10Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,368,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MCOLN1 NM_020533.3 missense, splice_region
• Scores: Splicing: ADA: 0.9912
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

Genes affected

MCOLN1 (HGNC:13356): (mucolipin TRP cation channel 1) This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV. [provided by RefSeq, Oct 2009]

LOC105372261 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity MCLN1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCOLN1	NM_020533.3	c.29C>T	p.Ser10Leu	missense_variant, splice_region_variant	1/14	ENST00000264079.11
LOC105372261	XR_936294.3	n.936+63G>A		intron_variant, non_coding_transcript_variant
LOC105372261	XR_936293.3	n.936+63G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCOLN1	ENST00000264079.11	c.29C>T	p.Ser10Leu	missense_variant, splice_region_variant	1/14	1	NM_020533.3	P1
MCOLN1	ENST00000596390.1	n.145C>T		splice_region_variant, non_coding_transcript_exon_variant	1/2	1
MCOLN1	ENST00000601003.1	c.29C>T	p.Ser10Leu	missense_variant, splice_region_variant	1/5	3
MCOLN1	ENST00000394321.9	n.109C>T		splice_region_variant, non_coding_transcript_exon_variant	1/13	2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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

GnomAD4 exome AF: 0.0000189 AC: 23 AN: 1216242 Hom.: 0 Cov.: 30 AF XY: 0.0000254 AC XY: 15 AN XY: 590298

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: 0.0000220

Gnomad4 OTH exome AF: 0.0000199

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.00

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: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.29C>T (p.S10L) alteration is located in exon 1 (coding exon 1) of the MCOLN1 gene. This alteration results from a C to T substitution at nucleotide position 29, causing the serine (S) at amino acid position 10 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.0025	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.73	N;.
REVEL	Benign	0.25
Sift	Benign	0.13	T;.
Sift4G	Uncertain	0.047	D;D
Polyphen		0.041	B;.
Vest4		0.30
MutPred		0.15		Loss of phosphorylation at S10 (P = 0.0143);Loss of phosphorylation at S10 (P = 0.0143);
MVP		0.83
MPC		0.38
ClinPred		0.59	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.26
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.78
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

LitVar

Other links and lift over

dbSNP: rs953773169; hg19: chr19-7587665;