rs587777070

Variant names:

• chr13-85795619-G-T
• rs587777070
• NM_032229.3:c.890C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_032229.3(SLITRK6):​c.890C>A​(p.Ser297*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,016 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLITRK6 NM_032229.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 5.44
• Publications: 4 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics, G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-85795619-G-T is Pathogenic according to our data. Variant chr13-85795619-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 88861.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032229.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLITRK6	NM_032229.3	MANE Select	c.890C>A	p.Ser297*	stop_gained	Exon 2 of 2	NP_115605.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLITRK6	ENST00000647374.2	MANE Select	c.890C>A	p.Ser297*	stop_gained	Exon 2 of 2	ENSP00000495507.1	Q9H5Y7
	SLITRK6	ENST00000643778.1		c.890C>A	p.Ser297*	stop_gained	Exon 3 of 3	ENSP00000496428.1	Q9H5Y7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461016 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 726816

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111506

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	High myopia-sensorineural deafness syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.4
Vest4		0.036
GERP RS		4.2
Mutation Taster		=11/189	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777070; hg19: chr13-86369754;