13-85794042-G-A

Position:

• chr13-85794042-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032229.3(SLITRK6):​c.2467C>T​(p.Leu823Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,088 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLITRK6 NM_032229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.55

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLITRK6	NM_032229.3	c.2467C>T	p.Leu823Phe	missense_variant	2/2	ENST00000647374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLITRK6	ENST00000647374.2	c.2467C>T	p.Leu823Phe	missense_variant	2/2		NM_032229.3	P1
SLITRK6	ENST00000643778.1	c.2467C>T	p.Leu823Phe	missense_variant	3/3			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460088 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726338

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces leucine with phenylalanine at codon 823 of the SLITRK6 protein (p.Leu823Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SLITRK6-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
Polyphen		1.0	D;D;D
Vest4		0.75
MutPred		0.44		Gain of methylation at K824 (P = 0.0321);Gain of methylation at K824 (P = 0.0321);Gain of methylation at K824 (P = 0.0321);
MVP		0.93
MPC		0.31
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.58
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-86368177;