19-7533651-A-T

Position:

• chr19-7533651-A-T

Variant summary

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

The ENST00000264079.11(MCOLN1):​c.1704A>T​(p.Gly568=) variant causes a splice region, synonymous 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCOLN1 ENST00000264079.11 splice_region, synonymous
• Scores: Splicing: ADA: 0.8766
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 0.360

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]

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
MCOLN1	NM_020533.3	c.1704A>T	p.Gly568=	splice_region_variant, synonymous_variant	13/14	ENST00000264079.11	NP_065394.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCOLN1	ENST00000264079.11	c.1704A>T	p.Gly568=	splice_region_variant, synonymous_variant	13/14	1	NM_020533.3	ENSP00000264079	P1
MCOLN1	ENST00000599334.1	c.433A>T	p.Lys145Ter	stop_gained, splice_region_variant	5/6	5		ENSP00000472176
MCOLN1	ENST00000394321.9	n.2019A>T		splice_region_variant, non_coding_transcript_exon_variant	12/13	2
MCOLN1	ENST00000602227.1	n.258A>T		splice_region_variant, non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucolipidosis type IV Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -
not provided, no classification provided	literature only	GeneReviews	-	Near the donor site of intron 13; creates an alternative donor splice site that results in a frameshift. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 29, 2022

Variant summary: MCOLN1 c.1704A>T (p.Gly568Gly) alters a non-conserved nucleotide located close to a canonical splice site (the last intron) and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5 splicing donor site. Four predict the variant creates a cryptic 5 donor site. Three predict the variant creates a cryptic 3 acceptor site. At least one publication reports this variant affects mRNA splicing proportionally (11% of the altered splicing form was detected) and results in the deletion of 4 bp at the RNA level, a shift of the reading frame (disrupting at the last 14 aa) (example: Dobrovolny_2006). The variant was absent in 247878 control chromosomes (gnomAD). c.1704A>T has been reported in the literature in-at least one individual who had a differential diagnosis for Mucolipidosis Type 4 (example: Dobrovolny_2006). These data do not allow any conclusion about variant significance. One submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: -2
DS_DL_spliceai		0.94		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs751298168; hg19: chr19-7598537;