rs35342386

chr13-85796287-G-Achr13-85796287-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032229.3(SLITRK6):c.222C>T(p.Asn74=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,611,612 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (38 hom., cov: 32)
  • Exomes 𝑓: 0.016 (210 hom.)
• Consequence: SLITRK6 NM_032229.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.49

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 13-85796287-G-A is Benign according to our data. Variant chr13-85796287-G-A is described in ClinVar as [Benign]. Clinvar id is 506092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0213 (3235/151982) while in subpopulation AFR AF= 0.0324 (1345/41488). AF 95% confidence interval is 0.031. There are 38 homozygotes in gnomad4. There are 1577 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLITRK6	NM_032229.3	c.222C>T	p.Asn74=	synonymous_variant	2/2	ENST00000647374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLITRK6	ENST00000647374.2	c.222C>T	p.Asn74=	synonymous_variant	2/2		NM_032229.3	P1
SLITRK6	ENST00000643778.1	c.222C>T	p.Asn74=	synonymous_variant	3/3			P1
SLITRK6	ENST00000645642.1	n.521-344C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3224 AN: 151866 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0202

GnomAD3 exomes AF: 0.0161 AC: 3964 AN: 246878 Hom.: 48 AF XY: 0.0149 AC XY: 2001 AN XY: 133906

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.0269

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00281

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.0161 AC: 23496 AN: 1459630 Hom.: 210 Cov.: 35 AF XY: 0.0154 AC XY: 11189 AN XY: 725972

Gnomad4 AFR exome AF: 0.0337

Gnomad4 AMR exome AF: 0.0254

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00395

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0213 AC: 3235 AN: 151982 Hom.: 38 Cov.: 32 AF XY: 0.0212 AC XY: 1577 AN XY: 74288

Gnomad4 AFR AF: 0.0324

Gnomad4 AMR AF: 0.0263

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0186 Hom.: 15

Bravo AF: 0.0223

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0131

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Asn74Asn in exon 2 of SLITRK6: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 3.12% (306/9798) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs35342386). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2019	- -

SLITRK6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	7.2
Dann	Benign	0.63

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

Other links and lift over

dbSNP: rs35342386; hg19: chr13-86370422; COSMIC: COSV68390225;