Genetic Variant SLITRK3:p.Arg861His (chr3-165188249-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001318810.2(SLITRK3):c.2582G>A(p.Arg861His) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SLITRK3
NM_001318810.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.88

Variant links:

Genes affected

SLITRK3 (HGNC:23501): (SLIT and NTRK like family member 3) This gene encodes a member of the Slitrk family of structurally related transmembrane proteins that are involved in controlling neurite outgrowth. The encoded protein contains two leucine-rich repeat (LRR) domains and a C-terminal domain that is partially similar to Trk neurotrophin receptor protein. Enhanced expression of this gene was found in tissue from several different types of tumors. Alternative splicing results in multiple transcript variants, all encoding the same protein. [provided by RefSeq, Jan 2016]

SLITRK3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07984716).

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK3	NM_001318810.2 link	c.2582G>A	p.Arg861His	missense_variant	Exon 2 of 2	ENST00000475390.2	NP_001305739.1	O94933
SLITRK3	NM_001318811.2 link	c.2582G>A	p.Arg861His	missense_variant	Exon 2 of 2		NP_001305740.1	O94933
SLITRK3	NM_014926.4 link	c.2582G>A	p.Arg861His	missense_variant	Exon 2 of 2		NP_055741.2	O94933

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLITRK3	ENST00000475390.2 link	c.2582G>A	p.Arg861His	missense_variant	Exon 2 of 2	1	NM_001318810.2	ENSP00000420091.1		O94933
SLITRK3	ENST00000241274.3 link	c.2582G>A	p.Arg861His	missense_variant	Exon 2 of 2	1		ENSP00000241274.3		O94933

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

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:

0.00000540

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151846

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74140

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2582G>A (p.R861H) alteration is located in exon 2 (coding exon 1) of the SLITRK3 gene. This alteration results from a G to A substitution at nucleotide position 2582, causing the arginine (R) at amino acid position 861 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

0.029

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.55

N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.26

N;N

REVEL

Benign

0.064

Sift

Uncertain

0.011

D;D

Sift4G

Benign

0.27

T;T

Polyphen

0.0

B;B

Vest4

0.35

MutPred

0.35

Loss of methylation at R861 (P = 0.0613);Loss of methylation at R861 (P = 0.0613);

MVP

0.26

MPC

0.25

ClinPred

0.53

GERP RS

4.9

Varity_R

0.076

gMVP

0.16

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