rs587777069

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_032229.3(SLITRK6):c.1240C>T(p.Gln414*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000298 in 1,612,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SLITRK6
NM_032229.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 5.91

Variant links:

Genes affected

SLITRK6 (HGNC:23503): (SLIT and NTRK like family member 6) This gene encodes a member of the SLITRK protein family. Members of this family are integral membrane proteins that are characterized by two N-terminal leucine-rich repeat (LRR) domains and a C-terminal region that shares homology with trk neurotrophin receptors. This protein functions as a regulator of neurite outgrowth required for normal hearing and vision. Mutations in this gene are a cause of myopia and deafness. [provided by RefSeq, Dec 2014]

SLITRK6 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.509 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-85795269-G-A is Pathogenic according to our data. Variant chr13-85795269-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-85795269-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLITRK6	NM_032229.3 linkuse as main transcript	c.1240C>T	p.Gln414*	stop_gained	2/2	ENST00000647374.2	NP_115605.2	Q9H5Y7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLITRK6	ENST00000647374.2 linkuse as main transcript	c.1240C>T	p.Gln414*	stop_gained	2/2		NM_032229.3	ENSP00000495507.1		Q9H5Y7
SLITRK6	ENST00000643778.1 linkuse as main transcript	c.1240C>T	p.Gln414*	stop_gained	3/3			ENSP00000496428.1		Q9H5Y7

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

151836

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248182

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134694

show subpopulations

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:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1460680

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726602

show subpopulations

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:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000151

AC:

AN:

151836

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74170

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000238

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

High myopia-sensorineural deafness syndrome

Pathogenic:3Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neurogenetic Laboratory, Second Faculty of Medicine, Charles University	Mar 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 30, 2020	- -

SLITRK6-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2023

The SLITRK6 c.1240C>T variant is predicted to result in premature protein termination (p.Gln414*). This variant has been reported as pathogenic for autosomal recessive deafness and myopia (Tekin. 2013. PubMed ID: 23543054; Morlet. 2013. PubMed ID: 23946138; Table S2, Safka Brozkova. 2021. PubMed ID: 34062854). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-86369404-G-A). Nonsense variants in SLITRK6 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2022

This sequence change creates a premature translational stop signal (p.Gln414*) in the SLITRK6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 428 amino acid(s) of the SLITRK6 protein. This variant is present in population databases (rs587777069, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with deafness and myopia syndrome (PMID: 23543054, 23946138). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88860). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.97

Vest4

0.15

GERP RS

5.6

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over