Genetic Variant SLITRK3:p.Gly867Cys (chr3-165188232-C-A) – 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.2599G>T(p.Gly867Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000706 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SLITRK3
NM_001318810.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.31

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=0.21022126).

BS2

High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK3	NM_001318810.2 link	c.2599G>T	p.Gly867Cys	missense_variant	Exon 2 of 2	ENST00000475390.2	NP_001305739.1	O94933
SLITRK3	NM_001318811.2 link	c.2599G>T	p.Gly867Cys	missense_variant	Exon 2 of 2		NP_001305740.1	O94933
SLITRK3	NM_014926.4 link	c.2599G>T	p.Gly867Cys	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.2599G>T	p.Gly867Cys	missense_variant	Exon 2 of 2	1	NM_001318810.2	ENSP00000420091.1		O94933
SLITRK3	ENST00000241274.3 link	c.2599G>T	p.Gly867Cys	missense_variant	Exon 2 of 2	1		ENSP00000241274.3		O94933

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

151740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.00

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251378

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000362

AC:

AN:

151856

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000477

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.000412

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2599G>T (p.G867C) alteration is located in exon 2 (coding exon 1) of the SLITRK3 gene. This alteration results from a G to T substitution at nucleotide position 2599, causing the glycine (G) at amino acid position 867 to be replaced by a cysteine (C). 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

0.22

BayesDel_addAF

Benign

-0.0091

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.69

.;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.21

T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.61

N;N

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.043

D;D

Polyphen

1.0

D;D

Vest4

0.67

MVP

0.67

MPC

0.79

ClinPred

0.17

GERP RS

5.8

Varity_R

0.30

gMVP

0.42

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