rs587777069

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 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

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

high myopia-sensorineural deafness syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLITRK6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 2 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 88860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK6	NM_032229.3 link	c.1240C>T	p.Gln414*	stop_gained	Exon 2 of 2	ENST00000647374.2	NP_115605.2	Q9H5Y7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLITRK6	ENST00000647374.2 link	c.1240C>T	p.Gln414*	stop_gained	Exon 2 of 2		NM_032229.3	ENSP00000495507.1		Q9H5Y7
SLITRK6	ENST00000643778.1 link	c.1240C>T	p.Gln414*	stop_gained	Exon 3 of 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

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248182

AF XY:

0.00000742

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 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

African (AFR)

AF:

0.00

AC:

AN:

33416

American (AMR)

AF:

0.00

AC:

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111416

Other (OTH)

AF:

0.00

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000151

AC:

AN:

151836

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41368

American (AMR)

AF:

0.00

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67908

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

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

Mar 30, 2021

Neurogenetic Laboratory, Second Faculty of Medicine, Charles University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 30, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLITRK6-related disorder

Pathogenic:1

Jun 28, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.97

PhyloP100

5.9

Vest4

0.15

GERP RS

5.6

Mutation Taster

=9/191

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over